MXPA05003456A - Pgd2 receptor antagonists for the treatment of inflammatory diseases. - Google Patents

Pgd2 receptor antagonists for the treatment of inflammatory diseases.

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Publication number
MXPA05003456A
MXPA05003456A MXPA05003456A MXPA05003456A MXPA05003456A MX PA05003456 A MXPA05003456 A MX PA05003456A MX PA05003456 A MXPA05003456 A MX PA05003456A MX PA05003456 A MXPA05003456 A MX PA05003456A MX PA05003456 A MXPA05003456 A MX PA05003456A
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MX
Mexico
Prior art keywords
phenyl
methyl
tetrahydro
group
benzoyl
Prior art date
Application number
MXPA05003456A
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Spanish (es)
Inventor
Harrison Sean
Original Assignee
Millennium Pharm Inc
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Publication date
Application filed by Millennium Pharm Inc filed Critical Millennium Pharm Inc
Publication of MXPA05003456A publication Critical patent/MXPA05003456A/en

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Abstract

Disclosed herein are compounds represented by Structural Formula (I), wherein the variables are defined herein. Also disclosed is the use of such compounds for inhibiting the G-protein coupled receptor referred to as chemoattractant receptor-homologous molecule expressed on Th2 ("CRTH2") for the treatment of inflammatory disorders.

Description

ANTAGONISTS OF THE RECEIVER OF PGD2 FOR THE TREATMENT OF INFLAMMATORY DISEASES BACKGROUND OF THE INVENTION PGD2 belongs to the class of prostaglandins derived from arachidonic acid. It is the predominant prostanoid produced by activated mast cells and is involved in the pathogenesis of allergic diseases such as asthma, rhinitis and atopic dermatitis (see Lewis et al., J. Immunol., 129: 1627 (1982), Hardy et al., N. Eng. J. Med. 311: 209 (1984), Murray et al., N. Eng. J. Med. 315: 800 (1986), Barry et al., Br. J. Pharmacol. 94: 773 (1988). PGD2 is a ligand for the DP receptor and was initially thought to induce all its biological actions through this receptor.The role of the DP receptor in allergic asthma has been demonstrated in mice deficient in DP (see Matsuoka et al., Science 287: 2013 (2000).) More recently, PGD2 was identified as a ligand for another G protein-coupled receptor termed "chemoattractant receptor-homologous molecule expressed on Th2" or simply "CRTH2" (see Tanaka et al., J. Immunol. 164: 2277 (2000), and U.S. Patent Application Publication No. US2002 / 0022218.) CRTh2 it is expressed in biosophiles, eosinophils and in Th2 type immune adjuvant cells. It has been shown that Th2 cells are involved in the orchestration of the allergic response (see Wills-Karp, Annual Review of Immunology, 17: 2b (1999)). PGD2 has been shown to induce chemotaxis in Th2 and eosinophil cells through the CRTH2 receptor, suggesting that CRTh2 can play a pro-inflammatory role in allergic diseases (see Hirai et al., J. Exp. Med. 193: 255 (2001)). It has also been shown that in patients with dermatitis there is an increase in circulating T cells expressing CRTh2 that is related to the severity of the disease (see Cosmi et al., Eur. J. Immunol., 30: 2972 (2000), Iwazaki. et al., J. Investigative Dermatology, 119: 609 (2002) .Thus, PGD2 is involved in various aspects of inflammation through its DP and CRTh2 receptors.Therefore, it is expected that CRTH2 antagonists and DPs are useful in the treatment of PGD2-mediated disorders Unfortunately, there are very few known CRTH2 inhibitors, if any.As a result, doctors will not be able to exploit these discoveries until new CRTH2 inhibitors are developed. OF THE INVENTION It has now been found that certain 1,2,3,4-tetrahydro-quinolin-4-yl-amines are potent inhibitors of CRTH2. For example, many compounds effectively inhibit the binding of PGD2 to HEK-293 cells that stably express CRTH2 at a Ki of less than 1.0 μ? . Based on this discovery, CRTH2 inhibitors, pharmaceutical compositions containing these inhibitors and methods for inhibiting CRTH2 activity in a subject in need of such treatment are described herein. One embodiment of the present inventions is a compound represented by Structural Formula (I): Ring A is an optionally substituted monocyclic aromatic ring; R is - ?? - R1; Rx is -X2-R4 and RJ is an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; or -NRXR3, taken together, is a heterocyclic group containing non-aromatic and optionally substituted nitrogen; X is -C (O) - or -C (R2) 2 -; each of Xx and X2 are independently a bond, S (0), S (0) 2, C (0) OR C (0) NH; R1 is H or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; with the proviso that when Xi is a bond, SO or S02, then R1 is not H; each R2 is independently -H, -X4-R8 or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R 4 is -H, -X 6 -R 10 or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; with the proviso that when X2 is a bond, SO or S02, then R4 is not H; each of X4 and Xs are independently a linear or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, -OH, = 0, C1-C3 alkoxy, nitro and cyano each of R5 and R6 is independently H or Ci- C3 alkyl; each of R7, R8, R9 and R10 are independently H, C (0) 0R "or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R" is H or R13; and R13 is Ci-C6 alkyl or C3-C8 cycloalkyl; Another embodiment of the method of the present invention is a method for inhibiting CRTH2 in a subject in need of inhibition of CRTH2. The method comprises the step of administering to the subject an effective amount of a compound represented by Structural Formula (I). Yet another embodiment of the present invention is a pharmaceutical composition. The pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I). The pharmaceutical compositions can be used in therapy, for example, to inhibit the activity of CRTH2 in a subject in need of such treatment. Yet another embodiment of the present invention is the use of a compound represented by Structural Formula (I) for the manufacture of a medicament for inhibiting the activity of CRTH2 in a subject in need of such treatment. The medicament comprises an effective amount of the compound. The disclosed compounds are effective inhibitors of CRTH2 activity and, as such, are expected to be useful in the treatment and prevention of diseases mediated by CRTH2 activity, including, but not limited to, inflammatory diseases such as asthma (allergic), atopic dermatitis, allergic rhinitis, systemic anaphylaxis or hypersensitivity responses, drug allergies (for example, to penicillin and cephalosporins), allergies to insect bites, chronic obstructive pulmonary disorder (COPD) and inflammatory dermatosis such as dermatitis, eczema, allergic dermatitis by contact and urticaria, atherosclerosis, restenosis, myositis (including polymyositis, dermatomyositis) and other diseases with an inflammatory component such as rheumatoid arthritis, osteoarthritis and inflammatory bowel disease (IBD). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to inhibitors of the homologous molecule of the chemoattraction receptor expressed in Th2 cells, also referred to herein as "CRTH2". Prostaglandin PGD2 is a neutral ligand for CRTH2, which binds and induces at least one of its pro-inflammatory activities. In this manner, the described compounds can be used to inhibit the activity of CRTH2; to inhibit the activity of PGD2 and to inhibit or treat (therapeutically or prophylactically) inflammatory disorders and allergic conditions mediated by CRTH2 and / or PGD2. Cells of the immune system that express CRTH2 include Th2 cells, eosinophils and basophils. In this way, the described compounds can be advantageously used to inhibit inflammatory disorders and allergic conditions mediated by these cells. In a first embodiment of the present invention, X is -CHR2-, R2 is -H, methyl or ethyl; R3 is a substituted or unsubstituted aromatic group; R5 and R6 are -H; and the rest of the variables of the Structural Formula (I) are as defined above. More preferably, the compound is represented by a structural formula selected from Structural Formulas (II) - (VIII): (III) The variables of the Structural Formulas (II) - (VIII) are as described above for the Structural Formula (I). The preferred values for these variables are provided below. The Phenyl Ring A is a substituted or unsubstituted phenyl group. Suitable substituents for the Phenyl Ring A are provided in the following section describing suitable aryl ring substituents. R1 in Structural Formulas (II) - (IV) and (VI) - (VIII) is -H, optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group, with the proviso that R1 in Structural Formulas ( III) is not -H; and R1 in the Structural Formula (V) is - (CH2) n -R13. R2 in Structural Formulas (II) - (VIII) is -H, methyl or ethyl. R3 in Structural Formulas (II) - (VIII) is an optionally substituted phenyl group. R4 in Structural Formulas (II) - (VI) and (VIII) is -H, -CH2C (0) R14, -CH2R15, -CH2OR14 or an optionally substituted C1-C3 alkyl group or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group, with the proviso that R4 in Structural Formula (VI) is not -H; and R4 in the Structural Formulas (VII) is - (CH2) n -R13. R 13 -H, -CH 2 C (0) R 14, -CH 2 R 15, -CH 2 OR 14 or an optionally substituted C 1 -C 3 alkyl group or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group.
Each R is independently a -H or an optionally substituted alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group. Each R15 is independently an optionally aromatic group, cycloalkyl group or non-aromatic heterocyclic group. n is O, 1, 2 or 3. The most preferred values for R1, R4 and R13 in Structural Formulas (II) - (VIII) are R1 and R13 and are a group, phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, thiazolyl, benzyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, -CH2- (W-pyridyl), -CH2-furanyl, thiophenyl -CH2-, -CH2-isoxazolyl, -CH2 - imidazolyl, -CH2-pyrazolyl, -CH2-pyrrolyl, -CH2-benzofuranyl, -CH2-tetrazolyl, -CH2-thiazolyl, -CH2- tetrazolyl, -CH2-benzothiazolyl, -CH2-benzimidazolyl, -CH2-0- phenyl, -CH2C (0) -phenyl, naphthalimidyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or optionally substituted cyclopropyl; and R4 is an alkyl group Ci-C4 alkyl, -CH20H, -CH2OCH3, -C¾OCH2CH3, CH2CH2OCH3, -CH2CH2OCH2CH3 or a phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, benzyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, -CH2- (N-pyridyl), -CH2-furanyl, -CH2 - thiophenyl, -CH2-isoxazolyl, imidazolyl CH2-, -CH2-pyrazolyl, -CH2-pyrrolyl, -CH2 -benzofuranilo, -CH2-tetrazolyl, -CH2-thiazol it, -CH2-tetrazolyl, -CH2-benzothiazolyl, -CH2-benzimidazolyl, -CH2-O-phenyl, -CH2C (0¡ - phenyl, naphthal imidilo, tetrahydrofuranyl, cyclohexyl , optionally substituted cyclopentyl or cyclopropyl, wherein R1, R4 and R13 are independently selected, and Ring A is optionally substituted at the five, six, seven and / or eight position Still more preferably, the compounds of the Structural Formulas (II) - (VIII) have one of the following characteristics and preferably to It has the following characteristics: The Phenyl A ring is optionally substituted in position five, six, seven and / or eight with R11; R1 is phenyl, thiophenyl, furanyl, pyridyl, oxazolyl, benzotriazole, pyrimidinyl, isoxazolyl or benzomorpholinyl, each group optionally substituted by R11; R3 is [R11] -phenyl; and R 4 is methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tere-butyl, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3. Especially preferred are compounds represented by Structural Formulas (II) - (VIII) in which the Phenyl Ring A is optionally substituted in the six and / or seven position with R11; R1 is thiophenyl, [R11] -thiophenyl, oxazolyl, [R11] -oxazolilo, pyridinyl, [R11] pyridinyl, benzotriazolyl, [R11] -benzotriazolilo, benzomorpholinyl, [R11] -benzomorfolinilo, phenyl or phenyl substituted with one to four groups selected from the group consisting of halo, -OR ° and -N (R11) 2, [R11] -oxazolyl, oxazolyl and R3 is phenyl substituted with one to four atoms groups selected from the group consisting of Br, Cl, CH3, -N (R16) 2; -NHC (0) OR ", -S (0) 2CH3, -S (O) 2N (R16) 2 and R13C (0) N (R16) 2. In the third preferred embodiment, Ring A in the Structural Formulas ( I) is a monocyclic heteroaryl group such as thiophene, furan, pyridine, pyrazole, pyrrole, [2, 3] pyrimidine, [3, 4] irimidine, [4, 5] pyrimidine, [5,6] pyrimidine, oxazole, isoxazole or 1, 2, 3-triazole, each group being optionally substituted with R 11. When Ring A has these values, then the compound preferably has at least one and preferably all of the following characteristics: X is -CHR2-, R2 is - H, methyl or ethyl, R5 and Rs are -H, and R3 is a substituted or unsubstituted phenyl group When the compound has at least one or all of the following characteristics, then preferably R1 and R4 are independently -H, -CH2C (0) R14, -CH2R15 or -CH2OR14 or an optionally substituted alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; and R14 and R15 are as described above for Structural Formula (II). When Ring A in Structural Formula (I) is a monocyclic heteroaryl, as described in the previous paragraph, the values that are normally selected for Xx and X2 are the following: Xi and X2 are both C (0); X1 is S (0) 2 and X2 is C (0); Xi is C (0) NH and X2 is C (0); Xx is a link and X2 is C (0); and X2 is C (0); Xx is C (0) and X2 is S (0) 2; Xi is C (0); and X is C (O) and X2 is a bond; or X is C (0) and X2 is C (0) NH. As an alternative, the Phenyl Ring A in the Structural Formulas (II) - (VIII) is replaced with one of the monocyclic aromatic groups described in the previous paragraph and the rest of the variables are as described above.
In a fourth preferred embodiment, R2 in Structural Formulas (I) - (VIII) is -H, C1-C4 alkyl, halogenated Ci-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, phenyl, substituted phenyl, - C (0) OR 16, benzyl, substituted benzyl or - (CH 2) n 0 (CH 2) m R 15 is C 1 -C 6 alkyl; n and m are positive integers such that n + m = 6; and the rest of the variables are as described above. Specific examples of compounds of the present invention are shown in Tables 1-6. Also described herein is a compound represented by Structural Formula (II) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds in Table 1-6 and R3 and R4 are as described above for Structural Formula (II). Also described herein is a compound represented by Structural Formula (II) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (II). Also described herein is a compound represented by Structural Formula (II) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (II). Also described herein is a compound represented by Structural Formula (III) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (III). Also described herein is a compound represented by Structural Formula (III) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (III). Also described herein is a compound represented by Structural Formula (III) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds of Table 1-6 and R3 and R4 are as described above for Structural Formula (III). Also described herein is a compound represented by Structural Formula (IV) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (IV).
Also described herein is a compound represented by Structural Formula (IV) and methods of using same to inhibit CRTH2, where R4 has the value corresponding to any of the compounds of Table 1 - 6 and R1 and R3 are as described above for Structural Formula (IV). Also described herein is a compound represented by Structural Formula (IV) and methods of using same to inhibit CRTH2, where R1 has the value corresponding to any of the compounds of Table 1 - 6 and R3 and R4 are as described above for Structural Formula (IV). Also described herein is a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, where RJ has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for the Structural Formula (V). Also described herein is a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (V). Also described herein is a compound represented by Structural Formula (V) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds of Table 1-6 and R3 and R4 are as described above for Structural Formula (V). Also described herein is a compound represented by Structural Formula (VI) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (VI). Also described herein is a compound represented by Structural Formula (VI) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (VI). Also described herein is a compound represented by Structural Formula (VI) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds of Table 1-6 and R3 and R4 are as described above for Structural Formula (VI). Also described herein is a compound represented by Structural Formula (VII) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (VII). Also described herein is a compound represented by Structural Formula (VII) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (VII). Also described herein is a compound represented by Structural Formula (VII) and methods of use thereof to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds of Table 1-6 and R3 and R4 are as described above for Structural Formula (VII). Also described herein is a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R3 has the value corresponding to any of the compounds of Table 1-6 and R1 and R4 are as described above for Structural Formula (VIII). Also described herein is a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R4 has the value corresponding to any of the compounds of Table 1-6 and R1 and R3 are as described above for Structural Formula (VIII).
Also described herein is a compound represented by Structural Formula (VIII) and methods of using same to inhibit CRTH2 in a subject in need of treatment and pharmaceutical compositions comprising the same, wherein R1 has the value corresponding to any of the compounds of Table 1-6 and R3 and R4 are as described above for Structural Formula (VIII). In certain aspects, the following compounds are excluded from the present invention: 2-methyl-N-phenyl-IV- [1,2,3,4-tetrahydro-2-methyl-1- (2-methyl-1-oxobutyl) -4-quinolinyl] -butamide; N- (1-Acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-heptamide; IV-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (1-oxo-3-phenylprop-l) -4-quinolinyl] -benzenepropanamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (3-nitrobenzoyl) -4 -quinolinyl] -hexanamide; N- [1,1'-biphenyl] -3-yl-W- [1,2,3,4-tetrahydro-l- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-nitrophenyl) -heptanamide; N- (1-benzoyl-1, 2, 3, 4-etrahydro-2-methyl-4-quinolinyl) -N- (4-methoxyphenyl) -2-methyl-propanamide; N- [1 - (4-fluorobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-butanamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -pentanamide; 2-ethyl-i \ - - [1- (2-ethyl-1-oxobutyl) -1,2,3,4-tetrahydro-2, 8 -dimethyl-4-quinol-inyl] -N- (2-methylphenyl) ) -butanamide; N- [1- [(4-fluorophenyl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-propanamide; N-phenyl-W- [1,2,3,4-tetrahydro-2-methyl-1- (4-nitrobenzoyl) -4-quinolinyl] -octanamide; N-cyclohexyl-4 - [(cyclohexylaminojcarbonyl] phenylamino] -3,4-dihydro-2-methyl-1 (2H) -quinolinecarboxamide; N- [1- (4-ethylbenzoyl) - 1, 2, 3, 4-tetrahydro-2, 8-dimethyl-4-quinolinyl] -N- (2-methylphenyl) -3- (4-nitrophenyl) -2 -propenaraide; 3- (4-methoxyphenyl) -N-phenyl-N [1,2,3,4-tetrahydro-1 - [3 - (4-methoxyphenyl) -1-oxo-2 -propeny1] -2-methyl--quinolinyl] -2-propenamide; 4 - [(ethoxyoxoacetyl) phenylamino] -3,4-dihydro-2-methyl-V-oxo-ethyl-1 (2H) -quinoline acetic acid ester; N- [1- (3-cyclohexyl-l-oxopropyl) 1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-cyclohexanopropanamide; 4 - (Acetylphenylamino) -3,4-dihydro-2-methyl-gamma-oxo-1 (2H) -quinoline-pentanoic acid; N- (1-benzoyl-1, 2,3,4-ehydro-2-methyl-4-quinolinyl) -2,2-dimethyl-N-phenyl-1-propanamide; N- (1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-pentanamide; N- [1- (2-furanylcarbonyl) -1,2,3,4-tetrahydro-2-methyl-4-quinol-inyl] -N-phenyl-acetamide; 2-methyl-N-phenyl-N- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinol inyl] -propanamide; N- [1 - [(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; 2,2,2-trifluoro-N-phenyl - [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; 2-ethyl-iV- [1- (2-ethyl-l-oxobutyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-butanamide; N- (1-benzoyl -1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl) -N- (3-methoxyphenyl) -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (1-oxohexyl) -4 -quinolinyl] -acetamide; 2V- (1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -iV-phenyl-2-thiophenecarboxamide; N- [1 - (2-f luorobenzoyl) - 1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-hexanamide; IV-phenyl-N- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-metyl-4-quinol ini 1] -hexanamide; N- [1- (cyclopropylcarbonyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-cyclopropanecarboxamide; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-methyl-1-phenyl) -acetamide; 2-methyl-N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (2-methyl-l-oxopropyl) -4-quinolinyl] -propanamide; N-phenyl-iV- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -2-1-iiophencarboxamide; 1- (3,5-dinitrobenzoyl) -N-formyl-1,2,3,4-tetrahydro-2-methyl-N-phenyl-4-quinoline; N- [1- (4-chloro-3-nitrobenzoyl) -1,2,4,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N-phenol-N- [1, 2, 3, 4-tetrahydro-2-methyl-l- (3-nitrobenzoyl) -4-quinolinyl] -acetamide; W-phenyl-N- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamid; N- [1 - (2-furanylcarbonyl) -1,2,4,4-tetrahydro-2-methyl-4-amino-1-phenyl-2-furancarboxamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1 - (1-oxopropyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-1 - [3- (4-methoxyphenyl) -l-oxo-2-propenyl] -2-methyl-4-quinolinyl] -acetamide; 3- (2-furanyl) -N- [1- [3- (2-furanyl) -l-oxo-2-propenyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-2-propenamide; N- [1 - [2 - (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] -1,2,3,4-tetrahydro-2 -methyl-4-quinolinyl] -N-phenyl-octanamide; iV- [1- (3-chlorobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; Relative stereochemistry of N-phenyl-N- [. { 2R, iS) - 1, 2, 3, 4 -tetrahydro-2-methi 1 - 1 - (1 -oxopropyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N- [. { 2R, AS) -1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -2-methyl-N-phenyl-propanamide; Relative stereochemistry of N- [(2 R, 4 S) -1-acet i 1, 1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-1-hexanamide; Relative stereochemistry of N- [(2R, 4 S) -1-ace il-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-1-propanamide; Relative stereochemistry of N- [(2 R, 45) -1-acetyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-heptanamide; Relative stereochemistry of iV- [(2 R, 4 S) -1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -2, 2-dimethyl-JV-phenyl-propanamide; JV- [1 - (3-fluorobenzoyl) -1,2,4,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; JV- [1 - [4 - (1,1-dimethylethyl) enzoyl] -1,2,3,4-tetrahydro-2-methyl-4-q-inolyl] -IV-phenyl-acetamide; JV- (1 -acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -2-methyl-iV-phenyl-propanamide; 2, 2, 2-trifluoro-JV-phenyl-JV- [1, 2, 3, 4-tetrahydro-2-methyl-1- (trifluoroacetyl) -4 -quinolinyl] -acetamide; Relative stereochemistry of JV- [(2R, 4 S) -l-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -2, 2-dimethyl-JV-phenyl-propanamide; Relative stereochemistry of JV- [(2R, 4 S) -1-acetyl-1, 2, 3, 4-tet ahydro-2-methyl-4-quinolinyl] -JV-phenyl-butanamide; Relative stereochemistry of JV- [(2 R, 4S) -1-benzoyl -1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-acetamide, · Relative stereochemistry of JV-phenyl- JV- [(2R, 4S) -1,2,3,4-tetrahydro-2-methyl-1- (1-oxo-heptyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N-phenyl-JV- [(2 R, 4S) -1, 2, 3, 4-tet ahydro-2-met i 1 - 1 - (1-oxohexyl) -4-quinolinyl] -acetamide; Relative stereochemistry of JV- [(2 R, 4 S) -l-acetyl-1,2,3,4-tetrahydro-2-met il-4-quinolinyl] -JV-phenyl -pent namide; JV- phenyl-JV- [1, 2, 3, 4-tetrahydro-2-met il-1 - (1-oxo-3-phenyl-2-propenyl) -4-quinolinyl] -acetamide; Relative stereochemistry of JV- [(2¾, 4 £) - 1 -benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-heptanamide; Relative stereochemistry of JV- [(2 R, 4 S) -l-acet l-l, 2,3,4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-acetamide; Relative stereochemistry of N- [(2 R, 4 S) -1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-pentanamide; iV- phenyl-JV- [1, 2, 3, 4-tetrahydro-2-methyl-1 - (tricyclo [3.3.1.13, 7] dec-1-ylcarbonyl) -4-quinolinyl] -acetamide; N-phenyl-IV- [1,2,3,4-tetrahydro-2-methyl-1- (1-oxopropyl) -4-quinolinyl] -propanamide IV-phenyl-N- [1, 2, 3, 4 tetrahydro - 2-met il-1 - (2-thienylcarbonyl) -4-quinolinyl] -acetamide; IV-phenyl-IV- [1,2,3,4-tetrahydro-1 - (-methoxybenzoyl) -2-methyl-4-quinolinyl] -2-furancarboxamide; IV-phenyl-IV- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N ~ [1 - (3, 5-dinitrobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; IV-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- 1 - (4-nitrobenzoyl) -4-quinolinyl] -acetamide; IV-phenyl-IV- [1,2,3,4-tetrahydro-1- (2-iodobenzoyl) -2-methyl-4-quinolinyl] -acetamide; JV-phenyl-N- [1, 2, 3, 4-tetrahydro-2-methyl-l- (2-methyl-1-1-oxopropyl) -4-quinolinyl] -acetamide; N-phenyl-iV- [1,2,3,4-tetrahydro-2-methyl-1 - [(4-methylphenyl) sulfonyl] -4-quinolinyl] -acetamide; JV-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1 - [(4-nitrophenyl) methyl] -4-quinolinyl] -aceamide; IV-phenyl-W- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- (1-acetyl 1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-butanamide; IV-phenyl-IV- [1,2,3,4-tetrahydro-2-methyl-1 - (1-oxobutyl) -4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-hexanamide; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -IV-phenyl-pentanamide; IV- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-propanamide; 1-benzoyl-1, 2, 3, 4-tetrahydro-4 - (N-phenylacetamido) quinalidine; N- (1-acetyl-6-bromo-1, 2,3,4-tetrahydro-2-met-il-4-quinol inyl) -IV-phenyl-1 -acetamide; IV- (1-acetyl-1, 2,3,4-tetrahydro-2-methyl-6-nitro-4-quinol il) -acetañil ida; IV- (1-Acetyl-6-chloro-1, 2,3,4-tetrahydro-2-methyl-4-quinolyl) -acetanilide; N- (1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl-j-N-phenyl-acetamide; N-. {1-benzoyl-6-chloro-1 , 2,3, 4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-1, 1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-butanamide; AT-phenyl-N- [1,2,3,4-tetrahydro-1- (3-fluorobenzoyl) -2-methyl-4-quinolinyl] -hexanamide. N- [1- (3-Chloro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-feml-acet mide; N- [1- (4-Fluoro-benzoyl) -2-methyl-6-nitro-1,2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-acetamide; (1-benzoyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl) -pheni-amide of pentanoic acid; N- (1-Benzoyl-6-chloro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide; N- [6-Chloro-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide N- [6-Bromo- l- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; N- (1-Benzoyl-6-nitro-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl) -N-phenyl-acetamide; N- (1-Benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -i? -phenyl-butyramide; N- [1 - (3-Methoxy-benzoyl) -2-me-il-1, 2,3,4-tetrahydro-quinol-4-yl] -2, 2-dimethyl-N-phenyl-propionamide. Many of the described CRTH2 inhibitors contain one or more chiral centers. The presence of chiral centers in a molecule gives rise to stereoisomers. For example, there is a pair of optical isomers, called "enantiomers", for each chiral center of the molecule; and there are a pair of diastereomers for each chiral center in a compound having two or more chiral centers. Even though the Structural Formulas (I) - (VIII) do not explicitly represent the stereochemistry, it is understood that these formulas encompass the free enantiomers of the corresponding optical isomer, racemic mixtures, mixtures enriched in one enantiomer relative to their corresponding optical isomer, a free diastereomer of other diastereomers, a pair of free diastereomers of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which a diastereomer is enriched in relation to the other diastereomers and mixtures of diastereomeric pairs in which a diastereomeric pair it is enriched in relation to the other diastereomeric pairs. A preferred diastereomeric pair is when R2 and NRXR3 in Structural Formulas (I) - (VIII) are cis one in relation to the other. By way of example, the cis diastereomeric pair for the compound represented by Structural Formula (II) is shown below in the Structural Formulas (IX) and (X): The preferred configuration for R2 and NRXR3 (represented by N (R3) (COR4) in the Structural Formulas (IX) and (X) is (2R, 4S), as shown in Structural Formula (IX). Structural Formula (IX) represents a preferred optical isomer for the compound represented by Structural Formula (II) Likewise, the corresponding optical isomer (2R, 4S) for the compounds represented by Structural Formulas (I) and (III) ) - (VIII) and Tables 1-6 are also specifically described The most preferred configuration for R2 and NRXR3 (represented by N (R3) (COR4)) in the Structural Formulas (IX) and (X) is (25, 4.R), which is shown in the Structural Formula (X). In this manner, Structural Formula (X) represents a more preferred optical isomer for the compound represented by Structural Formulas (I) and (III) - (VIII) and in Tables 1-6. As used herein, a structure representing an optical isomer or a reference to an optical isomer is intended to include enantiomeric mixtures that are enriched with the represented or referenced enantiomer relative to its optical isomer, eg, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or 99.5%. As used herein, a structure representing a diastereomeric pair or a reference to a diastereomeric pair is intended to include mixtures that are enriched with the diastereomeric pair represented or referenced in relation to the other diastereomers or diastereomeric pairs for the compound, eg, a molar excess of at least 50%, 75%, 90%, 95% 99% or 99.5%. The enantiomers of the present invention can be resolved by methods known to those skilled in the art, for example by formation of diastereomeric salts which can be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes that can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral medium, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. When the desired enantiomer is converted to another chemical entity by one of the separation methods described above, a further step is required to release the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, catalysts or solvents or by converting one enantiomer into the other by asymmetric transformation. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair can be separated as described above. The specific procedures for chromatographically separating the diastereomeric pairs of precursors used in the preparation of the compounds described herein are provided in Schemes 1 and 2. In certain cases, the compounds of the present invention may be associated in isolated form with a solvent or water, as in a "solvate" or "hydrate". References to the disclosed compounds or structural formulas representing the disclosed compounds are intended to include such solvates and hydrates. The term "aliphatic" as used herein means straight chain or branched hydrocarbons that are completely saturated or that contain one or more units of unsaturation, but are not aromatic. An aliphatic group is typically Ci_8, more typically Ci-6. For example, suitable aliphatic groups include linear or branched substituted or unsubstituted alkyl, alkenyl and alkynyl groups and hybrids thereof. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkylene" and "alkoxycarbonyl", used alone or as part of a larger moiety include linear and branched saturated chains containing from one to eight carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety include straight or branched chains containing from two to eight carbon atoms and one or more double and / or triple bonds, respectively. The term "cycloaliphatic" used alone or as part of a larger moiety includes cyclic C3-Ci0 hydrocarbons which are completely saturated or which may contain one or more units of unsaturation, but which are not aromatic. The cycloaliphatic groups are typically C3_10, more typically C3_7. A "cycloalkyl" is a cyclic aliphatic group that is completely saturated. "Alkoxy" means (alkyl) -O-; "alkoxyalkylene" means (alkyl) -O- (alkylene) such as methoxymethylene (CH3OCH2); "hydroxyalkyl" means an alkyl group substituted with hydroxy; "alkoxycarbonyl" means a carbonyl substituted with a carbonyl as in (alkyl) -0-C (O) -; and "aralkyl" means alkyl substituted with an aromatic group. A "C1-C4 aralkyl" group, for example, has a C1-C4 group substituted with an aromatic group.
The term "heteroatom" means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. In addition, the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl). The term "aromatic group" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl" includes carbocyclic aromatic ring groups and heteroaryl ring groups. The term "aromatic group" can be used interchangeably with the terms "aryl", "aryl ring" or "aromatic ring". Carbocyclic aromatic ring groups have only carbon atoms in the ring and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings condense each other. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term "carbocyclic aromatic ring", as used herein, is a group in which the aromatic ring is condensed to one or more non-aromatic rings (aliphatic or heterocyclic), such as in indanyl, phthalimidyl , naphthymidyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
The term "heteroaryl" or "heteroaromatic", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to a group of heteroaromatic rings having five to fourteen members, including monocyclic heteroaromatic rings and rings. polycyclic aromatics in which a monocyclic aromatic ring is condensed to one or more carbocyclic or aromatic heteroaromatic rings. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, IV-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5- oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidi lo, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl , benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridmyl or benzoisazolyl. Also included within the scope of the term "heteroaryl", as used herein, is a group in which a heteroaryl ring is condensed to one or more cycloaliphatic or non-aromatic heterocyclic groups where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolmyl, tetrahydroisoquinolinyl and pyrido [3,4-d] pyrimidmyl. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
The term "non-aromatic heterocyclic ring", used alone or as part of a larger moiety as in "heterocyclylalkyl"; refers to non-aromatic ring systems typically having five to fourteen members, preferably five to ten, wherein one or more ring carbons, preferably one to four, are each replaced with a hetero atom such as N, O or S. Examples of non-aromatic heterocyclic rings include 3-lJ-benzimidazol-2-one, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1, 3] -dioxalanyl, [1, 3] - dithiolanil, [1, 3] -dioxanil, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-1 iomorphol inyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrazolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanil, benzopyrrolidinyl, benzopiperidinyl, benzoxolani it, benzotiolanilo and benzotianilo. A "hydrocarbyl group" is a polymethylene group, i.e., - (CH2) n-, where n is a positive integer. Preferably, n is an integer from 1 to 6, more preferably from 2 to 4 and more preferably from 2 to 3. A "substituted hydrocarbyl" is a hydrocarbyl group in which one or more methylene hydrogen atoms are replaced with a substituent Suitable substituents are as described below for a substituted aliphatic group. Preferred substituents for the hydrocarbyl groups represented by X 3 -X 6 are halo, -OH, = 0, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro and cyano. A hydrocarbyl group can be optionally interrupted with one or more functional groups. A hydrocarbyl is interrupted with a functional group when one of the internal methylenes is replaced with the functional group. Examples of "interruption functional groups" include -0-, -S-, N (Ra) -, -S (O) -, -S02-, -C (0) -, -0C (0) -, - N (Ra) C (0) -, C (0) N (Ra) -, -S02N (Ra) - and -N (Ra) S02-. Ra is -H or a C1-C3 alkyl group. An aromatic group (including Ring A, aromatic carbocyclic, heteroaryl, aralkyl, aralkoxy, aryloxyalkyl and heteroaralkyl and the like) may contain one or more substituents. Examples of their suitable isomers on an unsaturated carbon atom of an aromatic group include a halogen, -R °, -0R °, -SR °, 1, 2 -methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O (Ph), -O (Ph) substituted, -CH2 (Ph), -CH2 (Ph) substituted, -CH2CH2 (Ph), -CH2C¾ (Ph) substituted , -N02, -CN, -N (R ') 2, -NR'C02R °, -NR'C (0) R °, -NR' NR 'C (0) R °, -N (R') C (0) N (R ') 2, -NR'NR'C (O) N (R') 2, -NR 'NR' C02R °, -C (0) C (0) R °, -C (O ) CH2C (0) R °, -C02R °, -C (0) R °, -C (0) N (R °) 2, -0C (O) N (R °) 2, -S (0) 2R °, -S02N (R ') 2, -S (0) R °, -NR' S02N (R ') 2, -NR'S02R °, -C (= S) N (R') 2, - (CH2 ) and N (R ') 2, -C (= NH) -N (R') 2, - (CH2) and NHC (0) R °, - (CH2) and NHC (0) CH (VR °) (R °) . R 'is R °, -C02R °, -S02R ° or -C (0) R ° and preferably hydrogen, aliphatic d_6, C02R °, S02R ° or C (0) R °. R ° is hydrogen or a substituted or unsubstituted group aliphatic, cycloaliphatic, aromatic, aralkyl, or a non-aromatic heterocyclic group and preferably hydrogen, Ci_s alkyl, phenyl (Ph), -CH2 (Ph), aralkyl, non-aromatic heterocyclic group or heteroaryl; and is 0-6; and V is a Ci-C6 alkylene group. Examples of substituents on the aliphatic group or the phenyl ring of R ° include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, aminoalkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl. An aliphatic group or a non-aromatic heterocycle may contain one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group of a non-aromatic heterocycle include those listed above for the unsaturated carbon of an aromatic group and the following: = 0, = S, = NNHR *, = N (R *) 2, = NNHC (0) R *, = NNHC02 (alkyl), = NNHS02 (alkyl) or = NR *. Each R * is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group represented by R * include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl . Suitable substituents on the substitutable nitrogen of a heteroaryl or non-aromatic heterocyclic group include -R +, -N (R +) 2, -C (0) R +, -C02 R +, -C (0) C (0) R +, -C (0) CH2 C (0) R \ -S02 R +, -S02 N (R +) 2, - C (= S) N (R +) 2, -C (= NH) -N (R +) 2 and -NR + S02 R +; where R + is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -O (Ph) CH2 (Ph) or a non-aromatic heteroaryl or heterocyclic group. Examples of substituents on the aliphatic group or the phenyl ring represented by R + include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl. . In addition, pharmaceutically acceptable salts of the compounds described herein are also included in the present invention and can be used in the compositions and methods described herein. For example, an acid salt of a compound containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counter ion such as chlorine, bromine, iodine, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [for example, (+) - tartrates, (-) - tartrates or mixtures thereof including racemic mixtures] , succinates, benzoates and salts with amino acids such as glutamic acid. The salts of the compounds containing a carboxylic acid or other acid functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt can be manufactured with a base that produces a pharmaceutically acceptable cation, including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts manufactured from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, β, β'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-. { 2-hydroxyethyl) amine, tri - (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, dehydroabietylamine,?,? ' -bis-dehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline and basic amino acids such as lysine and arginine. The compounds, pharmaceutical compositions and methods described can be used to inhibit the activity of CRTH2; to inhibit the activity of PGD2 including DP activity and to inhibit or treat (therapeutically or prophylactically) disorders with an inflammatory component and allergic conditions mediated by CRTH2 and / or PGD2 and / or DP. They can also be used to inhibit inflammatory disorders and allergic conditions mediated by Th2, eosinophil and basophil cells. Examples of allergic conditions for which the compounds, pharmaceutical compositions and methods described are believed to be particularly effective include allergic asthma, atopic dermatitis, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Other allergic conditions include systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin and cephalosporins), allergies to insect bites and dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis and urticaria. Examples of diseases with an inflammatory component for which the compounds, pharmaceutical compositions and methods described are believed to be particularly effective include rheumatoid arthritis, osteoarthritis, inflammatory bowel disease [e.g., such as ulcerative colitis, Crohn's disease, ileitis, celiac disease, non-tropical enteropathy, enteritis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis or pouchitis resulting from proctocolectomy, and ileoanal anastomosis] and skin disorders [eg, psoriasis, erythema, pruritis and acne]. Many autoimmune diseases also have an inflammatory component. Examples include multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis and other nephritis, autoimmune thyroiditis, Behcet's disease, and graft rejection (including allograft rejection or injure-versus-host disease). It is believed that the inflammatory component of these disorders is mediated, in the final part, by CRTH2. Diseases characterized by reperfusion have an inflammatory component that is believed to be mediated, in the final part, by CRTH2. Examples include stroke, cardiac ischemia and the like. The compounds and compositions described can also be used to treat these disorders. Other diseases and conditions with an inflammatory component that is believed to be mediated by CRTH2 include mastitis (mammary gland), vaginitis, cholecystitis, cholangitis and pericholangitis (bile duct and surrounding liver tissue), chronic bronchitis, chronic sinusitis, chronic inflammatory disease of the lung that results in interstitial fibrosis, such as interstitial lung diseases (ILD) (eg, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), hypersensitivity pneumonitis, collagen diseases, and sarcoidosis. Other diseases or conditions with inflammatory components that are amenable to treatment according to the procedures described herein include vasculitis (eg, necrotizing, cutaneous and hypersensitivity vasculitis), spondyloarthropathies, scleroderma, atherosclerosis, restenosis, and myositis (including polymyositis, dermatomyositis ), pancreatitis and insulin-dependent diabetes mellitus. A subject with one of the diseases or conditions mentioned above is said to be "in need of inhibition of C TH2". The subject with a disease or condition of this type is "treated" when at least one of the symptoms associated with the disease or condition is relieved (therapeutic treatment) or inhibited or prevented (prophylactic treatment) in whole or in part. A "subject" is a mammal, preferably a human being, but may also be an animal in need of veterinary treatment, for example, companion animals (eg, dogs, cats and the like), farm animals (e.g., cows) , sheep, pigs, horses and the like) and laboratory animals (for example, rats, mice, guinea pigs and the like). As indicated above, a "subject in need of inhibition of CRTH2" is a subject in which a beneficial therapeutic or prophylactic effect can be achieved by inhibiting the function or activity of CRTH2. An "effective amount" of the CRTH2 inhibitors described is the amount that inhibits the activity of CRTH2 in a subject in need of such inhibition, or that, when administered to a subject having a condition or disease that can be treated prophylactically or therapeutically. by inhibiting the activity of CRTH2, it ameliorates the symptoms of the disease, delays the onset of symptoms and / or increases longevity. The precise amount of the CRTH2 inhibitor administered to a subject will depend on the type and severity of the disease or condition and the characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. The dose may also vary according to the route of administration, which includes oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal. The person skilled in the art will be able to determine the appropriate doses depending on these and other factors. An "effective amount" typically ranges from about 0.01 mg / kg / day to about 100 mg / kg / day, preferably from about 0, 5 mg / kg / day and approximately 50 mg / kg / day. The CRTH2 inhibitors described herein, and the pharmaceutically acceptable salts thereof, can be used in pharmaceutical preparations together with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert fillers or solvents or diluents and sterile aqueous or organic solutions. The CRTH2 inhibitor will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. The techniques for formulation and administration of the compounds of the present invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). For oral administration, the CRTH2 inhibitor or salt thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, troches, powders, syrups, solutions, suspensions and the like. The tablets, troches, capsules and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other materials may be present as coatings or to modify the physical form of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring agent such as cherry or orange flavor. For parenteral administration, the described CRTH2 inhibitor, or salts thereof, may be combined with sterile aqueous or organic medium to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of pharmaceutically acceptable water-soluble salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under conventional conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. In addition, to the formulations described above, the compounds can also be formulated in the form of a depot preparation. Such long acting formulations can be administered by implantation, for example, subcutaneously or intramuscularly or by intramuscular injection. Thus, for example, in the form of an emulsion in an acceptable oil, or ion exchange resins, or in the form of soluble derivatives sparingly, for example, in the form of sparingly soluble salts. The invention is illustrated by the following examples which are not intended to limit it in any way. Experimental Section: General. All the reactions involving air sensitive reagents were carried out in a nitrogen atmosphere. The reagents were used as received from commercial suppliers unless otherwise indicated.
¾ NMR data were recorded using the Bruker UltraShield 300 MHz / 54 mm instrument equipped with the Bruker B-ACS60 Auto Sampler or the Varian 300 MHz instrument. Intermediates and final compounds were purified by flash chromatography using one of the following instruments: 1. Ultra-fast Biotage 4-channel Quad UV collector equipped with a Quad 1 Pump Module and Quad 12/25 Cartridge module. 2. Biotage Ultra-Fast 12-channel Quad UV collector equipped with a Quad 3 Pump Module and a Quad 3 Cartridge module. 3. ISCO combi ultra-fast chromatography instrument. The LC / MS spectra were obtained using a MicroMass LC Platform (Phenomenex C18 column, 5 microns, 50 x 4.6 mm) equipped with a Gilson 215 Liquid Handler. The conventional LC / MS conditions are as follows: Formic acid-Conventional conditions:% C (Water) 95, 0 Pump Gradient Time Table HP1100 LC% D 5.0 The Time Table of the Grade (Acetonitrile) contains 5 entries that are:% Acid 0.1 Time A% B% C% D% Flu Pres Formic or jo ion Flow (ml / min) 3,500 0.00 0, 0, 95, 5, 0 3.5 400 Time of 4.4 0 0 0 00 stop 3, 50 or, 00 0, 0 100 3.5 400 (min) 0, 0 00 Pressure min 0 4.30 o, o, 0.0 100 3.5 400 (bar) 0 0, or 00 Max pressure 400 4.40 o, 0, 95, 5.0 3.5 400 (bar) 0 0 0 00 Temperature 25, 0 5,00 o, 0, 95, 5,0 3,5 400 left of 0 0 0 00 Oven (° C) Temperature 25, 0 right of the Oven (° C) LC-MS data were acquired using the "Formic Acid Standard" procedure unless otherwise indicated.
Scheme 1 1 - . 1-trans 2 = tis (±) -Cis- and (+) -trans- (2-ethyl- 1, 2, 3, 4-etrahydro-quinolin-4-yl) -phenyl-amine (1) and (2) ) A 250 ml flask under an atmosphere of nitrogen was charged with aniline (1.0 g, 10.7 mmol, 1.0 equiv.), Acetaldehyde (0.599 ml, 10.7 mmol), benzotriazole (0.255 g, , 1 mmol, 0.2 equiv.) And dry toluene (100 ml) (Caution: an exotherm was observed). The benzotriazole / precipitated aldehyde adduct was observed immediately. The solution was allowed to stir at room temperature for 12 h. The precipitate formed after stirring overnight was filtered and washed with a minimum amount of diethyl ether, yielding exclusively the cis isomer. The trans isomer could be obtained by concentration of the filtrate. The residue was purified by an ultra-rapid Biotage system (95% hexane / 5% diethyl ether), yielding the cis and trans isomers in the form of a mixture. Then, the resulting oily residue was triturated with hexane to remove the cis isomer as a white solid and the filtrate was concentrated to give the trans isomer. Isomer (±) -cis - ¾ RN (CDCl3) d: 1.24 (d, 3H), 1.52 (c, 1H), 2.38 (dddd, 1H), 3.63 (m, 1H), 3.75 (sa, 2H, -NH), 4.83 (dd, 1H), 6.51 (d, 1H), 6.68 (m, 4H), 7.05 (m, 1H), 7.19-7.26 (m, 2H), 7.39 (d, 1H).
Isomer (±) -trans - XH NMR (CDC13) d: 1.22 (d, 3H), 1.56 (m, 1H), 2.20 (dt, 1H), 3.4 (m, 1H), 3.89 (br s, 2H, -NH), 4.55 (dt, 1H), 6.56 (dd, 1H), 6.66-6.75 (m, 4H), 7.08 (m, 1H ), 7, 19-7, 26 (m, 3H).
Scheme 2 Cis- (+) -1- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (3) A 30 ml flask in a nitrogen atmosphere was charged with ( ±) - cis- (2-methyl-1, 2, 3, 4-tetrahydro-quinol-4-yl) -phenyl-amine (0.520 g, 2.2 mmol, 1.0 equiv.) And acetic anhydride (0.209 mL, 2.2 mmol, 1.0 equiv.) And dry toluene (31 mL). The solution was heated at 50 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (70% hexane / 30% ethyl acetate), yielding cis-2-acetyl isomers in 67% yield. XH NMR (CDC13) d: 1.17 (d, 3H), 1.25 (c, 1H), 2.19 (s, 3H), 2.22 (sa, 1H), 2.65 (m, 1H ), 4.21 (dd, 1H), 4.96 (m, 1H), 6.65 (d, 2H), 6.75 (t, 1H), 7.12-7.33 (m, 6H) . Cis- (±) -furan-2-carboxylic acid (1-acetyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amide (4) A round-bottomed flask in a nitrogen atmosphere was charged with cis-1- (2-methyl-4-phenylamino-3, -dihydro-2f-quinolin-1-yl) -ethanone (0.163 g, 0.58 mmol, 1.0 equiv.) and 2-furoyl chloride (0.285 mL, 2.9 mmol, 5.0 equiv.) , pyridine (1.0 equiv.) and dry toluene (3 mL). The solution was heated at 90 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by a Biotage ultra-rapid system (50% hexane / 50% ethyl acetate), yielding the cis isomer in 40% yield. LH NMR (CDC13) d: 1.08 (d, 3H), 1.63 (m, 1H), 2.14 (s, 3H), 2.2 (br, 1H), 4.77 (m, 1H ), 5.75 (br s, 1H), 6.23 (dd, 1H), 7, 12-7.45 (m, 10H).
Scheme 3 (±) -Trans-1- (2-methyl-4-phenylamino-3,4-dihydro-2ff-quinolin-1-yl) -ethanone (5) A 30 ml flask in a nitrogen atmosphere was charged with ( ±) - trans- (2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.260 g, 1.1 mmol, 1.0 equiv.) And acetyl chloride ( 0.075 mL, 1.0 mmol, 0.95 equiv.) In pyridine (5 mL). The solution was allowed to stir at room temperature for 6 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (from 70% hexane / 30% ethyl acetate to 60% hexane / 40% ethyl acetate to 50% hexane / 50% ethyl acetate), producing the 2-acetyl trans isomers with a yield of 35%. ¾ RN (CDC13) d: 1.19 (d, 3H), 1.76 (m, 1H), 2.17 (s, 3H), 2.52 (dd, 1H), 4.60 (t, 1H ), 4.93 (m, 1H), 6.67 (d, 2H), 6.71 (t, 1H), 7.13-7.36 (m, 6H), 7.41 (d, 1H) . (L-acetyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amide of (+) - trans-furan-2-carboxylic acid (6) A round-bottomed flask in a nitrogen atmosphere was charged with (+) - trans- 1- (2-met-l, 4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (0.110 g, 0.39 mmol , 1.0 equiv.) And 2-furoyl eloride (0.193 mL, 1.9 mmol, 5.0 equi.), Pyridine (1.0 equiv.) And dry toluene (5 mL). The solution was heated at 50 ° C for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (30% hexane / 70% ethyl acetate to 50% hexane / 50% ethyl acetate), yielding the trans isomer in 34% yield. ¾ NMR (CDC13) d: 1.11 (d, 3H), 1.76 (s, 3H), 2.07 (dd, 1H), 2.37 (m, 1H), 5.00 (m, 1H ), 5.48 (d, 1H), 6.14 (dd, 1H), 6.29 (t, 1H), 6.90 (m, 1H), 6.99 (m, 1H), 7.22 -7.32 (m, 6H), 7, 34 (d, 1H), 7, 54 (dd, 1H). (+) -Cis-N- (l-Acetyl-2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl) -4-fluoro-W-phenyl-benzamide (7) A flask of 30 mi in a nitrogen atmosphere was charged with (±) -cis- (2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.520 g, 2.2 mmol, 1 , 0 equiv.) And acetic anhydride (0.209 mL, 2.2 mmol, 1.0 equiv.) And dry toluene (31 mL). The solution was heated at 50 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (70% hexane / 30% ethyl acetate), yielding cis-2-acetyl isomers in 67% yield. X H NMR (CDCl 3) d: 1.17 (d, 3 H), 1.25 (c, 1 H), 2.19 (s, 3 H), 2.22 (sa, 1 H), 2.65 (m, 1 H) ), 4.21 (dd, 1H), 4.96 (m, 1H), 6.65 (d, 2H), 6.75 (t, 1H), 7.12-7.33 (m, 6H) . A round-bottomed flask in a nitrogen atmosphere was charged with (±) - cis-1- (2-methyl-1,4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -ethanone (1.0 equiv.) and 2-fluorobenzoyl chloride (5.0 equiv.), pyridine (1.0 equiv.) and dry toluene (3 mL). The solution was heated at 90 ° C for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (50% hexane / 50% ethyl acetate), yielding the cis isomer in 40% yield. E NMR (CDC13) d: 1.1 (3H, d), 1.2 (1H, m), 2.1 (3H, s), 2.1 (1H, m), 4.8 (1H, m ), 5.4 (1H, m), 6.8 (2H, m), 6.9-7.4 (9H, m), 7.5 (1H, m). MS m / z: 403 (M + 1). (+) - Trans-N- (1-Acetyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -4-fluoro-IV-phenyl-benzamide (8) A flask of 30 mi in a nitrogen atmosphere was charged with (±) - trans- (2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -phenyl-amine (0.260 g, 1.1 mmol, 1 , 0 equiv.) And acetyl chloride (0.075 ml, 1.0 mmol, 0.95 equiv.) In pyridine (5 ml). The solution was allowed to stir at room temperature for 6 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (70% hexane / 30% ethyl acetate / 60% hexane / 40% ethyl acetate / 50% hexane / 50% ethyl acetate), yielding the isomers trans 2-acetyl with a yield of 35%. ¾ NMR (CDCl 3) d: 1.19 (d, 3H), 1.76 (m, 1H), 2.17 (s, 3H), 2.52 (dd, 1H), 4.60 (t, 1H), 4.93 (m, 1H), 6.67 (d, 2H), 6.71 (t, 1H), 7, 13-7.36 (m, 6H), 7.41 (d, 1H). A round bottom flask in a nitrogen atmosphere was charged with (±) - trans- 1- (2-methyl-4-phenylamino-3,4-dihydro-2H-quinol in-1-yl) -ethanone (1, 0 equiv.) And 4-fluorobenzoyl chloride (5.0 equiv.), Pyridine (1.0 equiv.) And dry toluene (5 ml). The solution was heated at 50 ° C for 5 h. The reaction mixture was evaporated in vacuo. The residue was purified by an ultra-rapid Biotage system (30% hexane / 70% ethyl acetate to 50% hexane / 50% ethyl acetate), yielding the trans isomer in 34% yield. XH NMR (CDC13) d: 1.2 (3H, d), 1.9 (3H, s), 2.0 (1H, m), 2.3 (1H, m), 5.0 (1H, m ), 6.2 (1H, m), 6.6-6.8 (4H, m), 7.1 (3H, m), 7.3 (4H, m), 7.6 (1H, m) . MS m / z: 403 (M + 1). General Procedure A Scheme 4 (±) -Cis-N- [1- (furan-2-carbonyl) -2-methyl-l, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (Al) A solution of (+) - cis- (2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (430 mg, 1.83 mmol) in dichloromethane (18 ml) at room temperature At room temperature, diisopropylethylamine (318 μl, 1.83 mmol) was added followed by 2-furoyl chloride. This was allowed to stir at room temperature for 12 h. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (80% hexanes / 20% ethyl acetate) to yield the amide (500 mg, 83%). To a solution of (+) - cis -furan-2-yl- (2-methyl-4-phenylamino-3,4-dihydro-2-yl-quinolin-1-yl) -methanone (360 mg, 1.0 mmol ) in methylene chloride (5 ml) was added diisopropylethylamine (1.9 ml, 10 mmol) followed by acetyl chloride (388 μl, 5 mmol). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) to yield the amide (230 mg, 57%). XH NMR (CDC13) d: 1.12 (d, 3H), 1.25 (t, 1H), 2.01 (s, 3H), 2.32 (m, 1H), 4.12 (sextuplet, 1H), 5.49 (sa, 1H), 6.22 (m, 2H), 6.84 (d, 1H), 7, 10 (t, 1H), 7.28-7.31 (m, 4H), 7.38 (m, 4H). MS m / z: 375 (M + 1). (+) -Cis-2-methoxy-W- [1- (3-methoxy-benzoyl) -2-methyl-1,2,2,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide ( A-2) (+) -Cis-2-methoxy-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for was performed and acetyl chloride for acetyl methoxychloride. ¾ NMR (CDCl 3) d: 1.14 (d, 3 H), 1.25 (t, 1 H), 2.33 (m, 1 H), 3.39 (s, 3 H), 3.60 (s, 3 H) ), 3.85 (d, 1H), 3.98 (d, 1H), 4.79 (sextuplet, 1H), 5.62 (sa, 1H), 6.53 (d, 1H), 6.72 (s, 1H), 6.81 (d, 1H), 6.92 (t, 1H), 7.08 (t, 1H), 7.16 (t, 1H), 7.29 (m, 2H) , 7, 35-7.42 (m, 3H). MS m / z: 445 (M + 1). (+) -Cis-4-chloro-iV- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-benzamide ( A-3) (±) -Cis-4-Chloro-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-benzamide following general procedure A, substituting 2-furoyl chloride for was performed and acetyl chloride for 4-chlorobenzoyl chloride. XH NMR (CDC13) d: 1.24 (d, 3H), 1.26 (m, 1H), 2.29 (m, 1H), 3.60 (s, 3H), 4.84 (sextuplet, 1H) ), 5.92 (br, 1H), 6.58 (d, 1H), 6.78 (d, 2H), 6.82 (s, 1H), 6.95 (t, 1H), 7.08 (t, 2H), 7.16-7.25 (m, 7H), 7.34 (d, 2H), 7.53 (d, 1H). MS m / z: 511, 0 (M + 1). (±) -Cis-N- [1- (3-Methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl-isobutyramide (A-4) It was made (±) - Cis-N- [1 - (3-methoxy-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide following general procedure A, substituting 2-furoyl chloride for was performed and acetyl chloride for isobutyryl chloride. X H NMR (CDCl 3) d: 1.14 (d, 9 H), 1.23 (t, 1 H), 2.28 (m, 1 H), 2.65 (sextuplet, 1 H), 3.65 (s, 3 H) ), 4.77 (sextuplet, 1H), 5.63 (sa, 1H), 6.51 (d, 1H), 6.67 (d, 1H), 6.78 (d, 1H), 6.86 (m, 2H), 7.01 (t, 1H), 7.14 (t, 1H), 7.24-7.37 (m, 6H).
MS m / z: 443, 0 (M + 1). (+) -Cis-N- [2-methyl-1- (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin--yl] -N-phenyl-acetamide (A-5) manufactured (±) - Cis-N- [2-methyl-1 - (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 2-thiophenecarbonyl chloride. Separated (±) - Cis-N- [2-methyl-1 - (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, giving (2i¾, 4S) - and (2S, 4i?) - JV- [2-methyl-1- (thiophene-2 - carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-11 and A-10, respectively). XH NMR (CDC13) d: 1.15 (d, 3H), 1.25 (m, 1H), 2.02 (s, 3H), 2.31 (m, 1H), 4.73 (sextuplet, 1H) ), 5.53 (sa, 1H), 6.68 (dd, 1H), 6.77 (t, 1H), 6.88 (d, 1H), 7.06 (t, 1H), 7.25 -7.32 (m, 4H), 7.39 (m, 4H). MS m / z: 391.0 (M + 1). (±) -Cis-N- [1- (4-tert-butyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A- 6) (±) -Cis-N- [1- (4-tert-butyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide following general procedure A, substituting 2-furoyl chloride for 4-erc-butylbenzoyl chloride. (±) -Cis-N- [1- (4-tert-butyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was separated by Chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - y. { 2S, 4i?) -cis-N- [1- (4-tert-butyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-8 and A-9, respectively). X H NMR (CDCl-i) d: 1.14 (d, 3 H), 1.16 (m, 1 H), 1.23 (s, 9 H), 2.04 (s, 3 H), 2.33 (m , 1H), 4.78 (sextuplet, 1H), 5.62 (sa, 1H), 6.53 (d, 1H), 6.91 (t, 1H), 7.15-7.40 (m, 11H). MS m / z: 441 (M + 1).
(+) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-7) (+) - Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,4,3-tetrahydro-quinolin-4-yl] -N-phenyl-1-acetamide was made following the General procedure A, substituting 2-furoyl chloride for 4-f luorobenzoyl chloride. (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinol in-4-yl] -N-phenyl-1-acetamide was separated by Chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2i?, 4S) - y (2S, 4i?) - cis-N- [1- (4 -fluoro -benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-acetamide (A-52 and A-44, respectively). XH N (CDC1 d: 1.13 (d, 3H), 1.25 (m, 1H), 2.03 (s, 3H), 2.32 (m, 1H), 4.78 (sextuplet, 1H) , 5.62 (sa, 1H), 6.47 (d, 1H), 6.83-6.95 (m, 3H), 7.16-7.40 (m, 9H) MS m / z: 403 (M + 1). (+) -Cis-N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-q inolin-4-yl ] -N-phenyl-acetamide (A-12) (+) - Cis-N- [2-methyl-1 - (5-methyl-iofen-2-carbonyl) -1,2,3, 4-tetrahydro was manufactured -quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 5-methyl-2-thiophenecarbonyl chloride. (+) - Cis-N- [2-methyl - 1 - (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide by chiral HPLC using a Chiralcel OD column and eluting with hexane at 90% / isocratic system of 10% ethanol, giving (2i?, 4S) - and (2S, 4i?) - ci sN- [2-methyl-1 - (5-methyl-thiophene-2-carbonyl) -1 , 2, 3, 4-tetrahydro-quinol-4-yl] -N-phenyl-1-acetamide (A-59 and A-60, respectively). H NMR (CDC13) d: 1.07 (m, 1H), 1.12 (d, 3H), 2.01 (s, 3H), 2.31 (m, 1H), 2.39 (s, 3H) ), 4.69 (sextuplet, 1H), 5.50 (sa, 1H), 6.44 (s, 1H), 6.51 (d, 1H), S, 94 (d, 1H), 7.09 (t, 1H), 7.21-7.30 (m, 3H), 7.39-7.41 (m, 4H). MS m / z: 405 (M + 1) (±) -Cis-N- [2-methyl-1- (4-methyl-2-pyrazin-2-yl-thiazole-5-carbonyl) -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-13) (±) -Cis-N- [2-ethyl-1- (4-methyl-2- pyrazin-2-yl-thiazole-5-carbonyl} -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-methyl-2- (2-pyrazinyl) -1,3-thiazole-5-carbonyl chloride XH NMR (CDC13) d: 1.18 (d, 3H), 1.77 (br, 1H), 2 , 03 (s, 3H), 2.10 (s, 3H), 2.32 (m, 1H), 4.79 (sextuplet, 1H), 5.50 (sa, 1H), 6.74 (d, 1H), 7.03 (t, 1H1, 7.26-7.41 (m, 7H), 8, 55 (d, 1H), 9, 32 (s, 1H) MS m / z: 484 ( M + 1). (+) -Cis-N- [2-methyl-1- (3-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -iV - phenyl-acetamide (A-14) (±) - Cis-N- [2-methyl-1- (3-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinol in 4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3-methyl-2-thiophenecarbonyl chloride. XH NMR (CDCl 3) d: 1.13 (d, 3H), 1.16 (m, 1H), 1.80 (s, 3H), 2.00 (s, 3H), 2.29 (m, 1H), 4.73. (sextuplet, 1H), 5.49 (sa, 1H), 6.56 (d, 1H), 6.66 (d, 1H), 6.97 (t, 1H), 7.16 (d, 2H) , 7.25 (d, 2H), 7.32 (d, 1H), 7.38 (sa, 3H). MS m / z: 405 (M + 1). (±) -Cis-N- [2-methyl-l- (5-phenyl-thiophene-2-carbonyl) -1,2, 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-15) (±) - Cis-N- [2-methyl-1 - (5-phenyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-1] - N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 5-phenyl-2-thiophenecarbonyl chloride. H NMR (CDC13) d: 1.15 (d, 3H), 1.17 (m, 1H), 2.03 (s, 3H), 2.31 (m, 1H), 4.73 (sextuplet, 1H), 5.55 (sa, 1H), 6.59 (s, 1H), 6.95 (d, 2H), 6, 99 (s, 1H), 7.10 (t, 1H), 7.26-7.44 (m, 9H), 7.53 (d, 2H). MS m / z: 467 (M + 1). (+) -Cis-N- [2-methyl-l- (4-methyl-2-phenyl-thiazole-5-carbonyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl-acetamide (A-16) (±) -Cis-N- [2-methyl-1- (4-methyl-2-phenyl-thiazole-S-carbonyl) -1,2,3, 4-tetrahydro was manufactured -quinolin-4-yl] -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 4-methyl-2-phenyl-1,3-thiazol-5-carbonyl chloride. X H NMR (CDCl 3) d: 1.16 (d, 3 H), 1.18 (m, 1 H), 2.03 (s, 3 H), 2.14 (s, 3 H), 2.32 (m, 1 H) ), 4.74 (sextuplet, 1H), 5.53 (sa, 1H), 6.77 (d, 2H), 7.04 (t, 1H), 7.24-7.28 (m, 3H) , 7.38-7.40 (m, 7H), 7.83 (d, 2H). MS m / z: 482 (M + 1). (±) -Cis-N- [2-methyl-l- (4-methyl- [1,2,3] thiadiazole-5 -carbonyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-17) (+) -Cis-N- [2-methyl-1- (4-methyl- [1,2,3] thiadiazole-5-carbonyl) -1,2 was manufactured , 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-methyl- [1,2,3] thiadiazol-5-carbonyl chloride . X H NMR (CDCl 3) d: 1.17 (d, 3 H), 1.21 (m, 1 H), 2.01 (s, 3 H), 2.36 (s, 3 H), 2.24 (m, 1 H) ), 4.81 (sextuplet, 1H), 5.48 (sa, 1H), 6.52 (d, 1H), 6.98 (t, 1H), 7.22-7.26 (m, 3H) 7.37-7.42 (m, 4H). MS m / z: 407 (M + 1). (±) -Cis-N- [1- (5-isopropyl-thiophene-2-carbonyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-19) (±) -Cis-N- [1- (5-isopropyl-thiophene-2-carbonyl) -2-araethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] - iV-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 5-isopropylthiophene carbonyl chloride. XH NMR (CDC13) d: 1.11 (d, 3H), 1.15 (m, 1H), 1.19-1.25 (m, 6H), 2.01 (s, 3H), 2.30 (m, 1H), 2.70 (m, 1H), 4.69 (sextuplet, 1H), 5.51 (sa, 1H), 6.45 (s, 1H), 6.55 (s, 1H) , 6.87-6.95 (m, 1H), 7.04-7.08 (m, 1H), 7.27 (s, 3H), 7.38 (s, 4H). MS m / z: 433 (M + 1). (±) -Cis-N- [2-methyl-1- (3,4,5-trifluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide ( A-20) (±) -Cis-N- [2-methyl-1 - (3, 4, 5-trifluoro-benzoyl) - 1, 2, 3, 4-tetrahydro-quinolin-4-yl] - N-phenyl-acetamide following general procedure A, substituting 2-fluoride chloride for 3, 4, 5-trifluorobenzoyl chloride. X H NMR (CDCl 3) d: 1.12 (d, 3 H), 1.21 (m, 1 H), 2.03 (s, 3 H), 2.31 (m, 1 H), 4.71 (sextuplet, 1 H) ), 5.55 (sa, 1H), 6.50 (d, 1H), 6.82 (t, 1H), 6.99 (t, 1H], 7.06 (t, 1H), 7.24 -7.27 (m, 3H), 7.39 (m, 3H), 7.46 (d, 1H) MS m / z: 439 (M + 1). (+) -Cis-N- [1 - (4-Fluoro-3-methyl-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-21) It was manufactured (±) - Cis -N- [1 - (-fluoro-3-methyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -JV-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 4-fluoro-3-methylbenzoyl chloride. NMR (CDC13) d: 1.12 (d, 3H), 1.22 (m, 1H), 2.04 (s, 3H), 2.15 (s, 3H), 2.29 (m, 1H), 4.75 (sextuplet, 1H), 5.60 (sa, 1H), 6.50 (d, 1H), 6, 73 (t, 1H), 6.86 (s, 1H), 6.93 (t, 1H), 7, 15-7.39 (m, 8H). MS m / z: 417 (M + 1). (±) -Cis-N- [1- (4-fluoro-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-22) (±) -Cis-N- [1- (4-fluoro-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-fluoro-3- (trifluoromethyl) -benzoyl chloride. 2 H NMR (CDCl 3) d: 1.15 (d, 3 H), 1.24 (m, 1 H), 2.04 (s, 3 H), 2.33 (m, 1 H), 4.75 (sextuplet, 1 H) ), 5.58 (sa, 1H), 6.46 (d, 1H), 6.87-6.96 (m, 3H), 7.10-7.41 (m, 6H), 7.49 ( d, 1H), 7, 74 (d, 1H). MS m / z: 471 (M + 1). (±) -Cis-N- [1- (3-chloro-4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4 -tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-23) (+) -Cis-N- [1- (3-chloro-4-fluoro-benzoyl) was manufactured -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride of 3-chloro-4-fluorobenzoyl chloride . X H NMR (CDCl 3) d: 1.13 (d, 3 H), 1.24 (ra, 1 H), 2.04 (s, 3 H), 2.31 (m, 1 H), 4.76 (sextuplet, 1 H) ), 5.59 (sa, 1H), 6.50 (d, 1H), 6.85 (d, 2H), 6.96 (t, 1H), 7.21 (t, 1H), 7.27 (m, 2H), 7.39 (m, 4H), 7.50 (d, 1H). MS m / z: 437 (+ l). (±) -Cis-N- [2-methyl-1- (2,4,6-trifluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide ( A-24) (±) - Cis-N- [2-methyl-1 - (2,4,6,6-trifluoro-benzoyl) - 1, 2, 3, 4-tetrahydro-quinolin-4-yl] - N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 2,4,6-trifluorobenzoyl chloride. XH NMR (CDC13) d: 1.13 (d, 3H), 1.21 (m, 1H), 2.05 (s, 3H), 2.29 (m, 1H), 4.86 (sextuplet, 1H), 5.45 (sa, 1H), 6.35 (t, 1H), 6.70 (d, 2H), 6, 95 (t, 1H), 7.2-7.5 (m, 7H). MS m / z: 439 (M + 1). (+) -Cis-N- [1- (4-chloro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] - -phenyl-propionamide (A-25) manufactured (±) - Cis-N- [1- (4-chloro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the general procedure A, substituting 2-furoyl chloride for 4-chlorobenzoyl chloride and acetyl chloride for propionyl chloride. X H NMR (CDCl 3) d: 1.09 (t, 3 H), 1.12 (d, 3 H), 1.22 (m, 1 H), 2.23 (m, 3 H), 4.73 (sextuplet, 1 H) ), 5.58 (sa, 1H), 6.46 (d, 1H), 6.78 (d, 1H), 6.88 (t, 1H), 6.98 (t, 1H), 7.15 (t, 1H), 7.18-7.44 (m, 8H). MS m / z: 433 (M + 1). (+) -Cis-N- [2-methyl-1- (4-trifluoromethoxy-benzoyl) -1,2,3,4-tetra-idro-quinolin-4-yl] -N-phenyl-acetamide (A-26) ) (+) - Cis-JV- [2-methyl-1 - (4-trifluoromethoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following general procedure A, substituting 2-furoyl chloride for 4 - (trifluoromethoxy) benzoyl chloride. X H NMR (CDCl 3) d: 1.16 (d, 3 H), 1.24 (m, 1 H), 2.28 (m, 3 H), 4.78 (sextuplet, 1 H), 5.61 (sa, 1 H) ), 6.46 (d, 1H), 6.91 (t, 1H), 6.92 (t, 1H), 7.02 (d, 2H), 7.18 (t, 1H), 7.23 -7.27 (m, 4H), 7.33 (d, 1H), 7.39 (s, 3H). S m / z: 469 (M + l). (+) -Cis-N- [2-methyl-1- (3-trifluoromethoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-27) ) (±) - Cis-N- [2-methyl-1- (3-trifluoromethoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following general procedure A, substituting 2-furoyl chloride for 3- (tri-fluoromethoxy) benzoyl chloride. LH NMR (CDCl 3) d: 1.14 (t, 3H), 1.15 (d, 3H), 1.25 (m, 1H), 2.25 (m, 3H), 4.78 (sextuplet, 1H) ), 5.59 (sa, 1H), 6.46 (d, 1H), 6.91 (t, 1H), 6.95 (d, 1H), 7.12-7.27 (m, 6H) , 7, 34 (d, 1H), 7.39 (s, 3H). MS m / z: 469 (M + 1). (+) - Cis-N- [2-methyl-1- (3-phenyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-28) (±) - Cis-N- [2-methyl-1- (3-phenyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinol in-4-yl] was made -IV-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3-phenyl-5-isoxazolecarbonyl chloride and acetyl chloride for propionyl chloride. ? NMR (CDC13) d: 1.14 (t, 3H), 1.19 (d, 3H), 1.61 (m, 1H), 2.24 (m, 3H), 4.78 (sextuplet, 1H) , 5.49 (sa, 1H), 6.34 (sa, 1H), 6.85 (d, 1H), 7.10 (t, 1H), 7.26 (s, 3H), 7.32 ( t, 1H), 7.40 (m, 6H), 7.67 (s, 2H).
MS m / z: 466 (M + 1). (±) -Cis-iV-. { 2-methyl-l- [4- (5-methyl-tetrazol-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N- phenyl-pro-ionamide (A-29) It was made (±) - Cis-N-. { 2-methyl-1- [4 - (5-methyl-tetrazol-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4- (5-methyl-l, l-tetrazol-1-yl) -benzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDC13) d: 1.16 (t, 3H), 1.17 (d, 3H), 1.24 (m, 1H), 2.26 (m, 3H), 2.55 (s, 3H), 4.82 (sextuplet, 1H), 5.64 (sa, 1H), 6.50 (d, 1H), 6, 94 (t, 1H), 7.21-7.41 (m, 11H). MS m / z: 481 (M + 1). (+) -Cis-N-. { 1- [3- (4-chloro-phenyl) -isoxazole-5-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-30) It was manufactured (±) - Cis-N-. { 1 - [3 - (4-Chloro-phenyl) -isoxazole-5-carbonyl] -2-me-il-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 3- (4-chlorophenyl) -5-isoxazolecarbonyl chloride and propionyl chloride for acetyl chloride. 2 H NMR (CDCl 3) d: 1.21 (m, 6 H), 1.24 (m, 1 H), 2.23 (m, 3 H), 4.76 (sextuplet, 1 H), 5.48 (br s, 1 H ), 6.28 (s, 1H), 6.84 (d, 1H), 7.07 (m, 2H), 7.26-7.67 (m, 7H), 7.78 (d, 1H), 8, 03 (t, 2H). MS m / z: 500 (M + l). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -2-hydroxy-W-phenyl-acetamide ( A-31) (±) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -2-hydroxy-N- was made phenyl acetamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for acetoxyacetyl chloride. ¾ NMR (CDCl 3) d: 1.13 (d, 3H), 1.22 (m, 1H), 2.39 (m, 1H), 3.42 (s, 1H), 3.85 (d, 1H ), 4.04 (d, 1H), 4.77 (sextuplet, 1H), 5.54 (sa, 1H), 6.49 (d, 1H), 6.85 (t, 2H), 6. 94 (t, 1H), 7.18-7.27 (m, 5H), 7.33 (d, 1H), 7.43 (s, 3H).
MS m / z: 419 (M + 1). (±) -Cis-N- [1- (líT-indole-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide (A- 32) (±) - Ci sN- [1 - (1H-indole-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was manufactured following general procedure A substituting 2-furoyl chloride for indole-2-carbonyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.25 (t, 3 H), 1.26 (d, 3 H), 1.27 (m, 1 H), 2.36 (m, 3 H), 4.86 (sextuplet, 1 H) ), 5.62 (sa, 1H), 5. 95 (s, 1H), 7.11 (t, 1H), 7.18 (t, 2H), 7.29 (t, 1H), 7.37 (m, 4H), 7.44-7, 55 (m, 5H). MS m / z: 438 (M + 1). (±) -Cis-N- [2-methyl-1- (4-pyrazol-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-33) (+) - Cis-N- [2-met i 1 - 1 - (4-pyrazol-1-yl-benzoyl) - 1, 2, 3, 4-tetrahydro-quinol in-4 - Figure imgf000017_0001] -IV-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4- (lH-pyrazol-1-yl) -benzole chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.03 (t, 3 H), 1.11 (d, 3 H), 1.20 (m, 1 H), 2.19 (m, 3 H), 4.73 (sextuplet, 1 H) ), 5.62 (br s, 1H), 6.39 (s, 1H), 6.48 (d, 1H), 6.86 (t, 1H), 7.10-7.34 (m, 9H) , 7.48 (d, 2H), 7.65 (s, 1H), 7.81 (s, 1H). MS m / z: 465 (M + 1). (±) -Cis-N- [1- (benzofuran-2 -carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-34) (+) - Cis-N- [1- (benzofuran-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -IV-phenyl-propionamide was made following the procedure General A substituting 2-furoyl chloride for 2-benzofuran carbonyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDC13) d: 1.04 (t, 3H), 1.07 (d, 3H), 1.18 (m, 1H), 2.19 (m, 3H), 4.69 (sextuplet, 1H) ), 5.54 (br s, 1H), 6.41 (d, 1H), 6.70-7.39 (m, 12H), 7.43 (d, 1H). MS m / z: 439 (M + 1). (±) -Cis-N- [1- (3-chloro-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-35) (±) - Cis-N- [1- (3-chloro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure General A substituting 2-furoyl chloride for 3-chlorobenzoyl chloride and propionyl chloride for acetyl chloride. LH NMR (CDCl 3) d: 1.09 (t, 3H), 1.12 (d, 3H), 1.22 (m, 1H), 2.23 (m, 3H), 4.73 (sextuplet, 1H) ), 5.58 (sa, 1H), 6.46 (d, 1H), 6.78 (d, 1H), 6.88 (t, 1H), 6.98 (t, 1H), 7.15 (t, 1H), 7.18-7.44 (m, 8H). MS m / z: 433 (M + 1). Ethyl ester of (+) - cis- acid. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic (A-36) Ethyl ester of (±) - Cis- was manufactured. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2-yl-quinoline-1 -carbonyl] -phenoxy} -acetic from (±) -N- [1- (4-Hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -W-phenyl-propionamide. (±) -N- [1- (4-Ethoxy-benzoi-1) -2-methyl-1,4,3-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide (0.147 g) was dissolved in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 0.021 g) was added and the mixture was allowed to stir for 30 min. Ethyl-bromoacetate (0.065 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (gradient of 80/20 hexanes / ethyl acetate-50/50 hexanes / ethyl acetate) yielding the product (130 mg, 73%). ? NMR (CDC13) d: 1.08-1.16 (m, 9H), 1.21 (t, 1H), 2.24 (m, 3H), 4.09 (c, 2H), 4.53 ( s, 2H), 4.74 (sextuplet, 1H), 5.59 (sa, 1H), 6.48 (d, 1H), 6.67 (d, 2H), 6.89 (t, 1H), 7, 11-7, 37 (m, 9H). MS m / z: 500 (M + l). (±) -Cis-N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-Eenyl-propionamide (A-37) It was made (±) - Cis-N- [1 - (4-hydroxy-benzoyl) -2-methyl -1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide from (+) - cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2 , 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide substituting 3-chlorobenzoyl chloride. (±) -Cis-N- [1- (A-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-propionamide (0.548) was dissolved g, 0.001 mol) in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added thereto.; the reaction was allowed to stir at room temperature for 4 h or until no starting material remained. The reaction was carefully washed with sat. NaHCO 3. and brine. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The phenol was concentrated and the residue was purified by Biotage flash chromatography using 100% EtOAc to give a white solid, 68% yield. XH NMR (CDC13) d: 1.09 (d, 3H), 1.11 (t, 3H), 1.19 (m, 1H), 2.26 (m, 3H), 4.74 (sextuplet, 1H) ), 5.54 (sa, 1H), 6.46 (d, 1H), 6.53 (d, 1H), 6.96 (t, 1H), 7.14-7.40 (m, 9H) .
MS m / z: 415 (M + 1) (±) -Cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-38) (±) - Cis-N- [1- (4-methoxy-benzoi-1) -2-methyl-1,2,3,4-tetrahydro-quinolin-4 was made - il] -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-methoxybenzoyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.12 (d, 3 H), 1.15 (t, 3 H), 1.17 (m, 1H), 2.23 (m, 3H), 3.74 (s, 3H), 4.74 (sextuplet, 1H), 5.61 (sa, 1H), 6.52 (d, 1H), 6, 67 (d, 2H), 6.92 (d, 1H), 7.17 (d, 2H), 7.25-7.34 (m, 4H), 7.39 (sa, 3H). MS m / z: 429 (M + 1). Acid (+) -Cis- -. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2-yl-quinoline-1-carbonyl] -phenoxy} -acetic (A-39) Acid (+) - Cis- was made. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic from ethyl ester of (+) - cis- acid. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl-1] -phenoxy} -acetic Ethyl ester of (+) -Cis- acid was dissolved. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic in ethanol (5 ml) and 0.5 ml of 1 N NaOH was added at room temperature. The reaction was allowed to stir for 4 h. The ethanol was removed in vacuo and the aqueous solution was acidified with 1 N HCl, giving a white precipitate which was filtered, giving the desired product in 88% yield. X H NMR (CDCl 3) d: 1.12 (d, 3 H), 1.16 (t, 3 H), 1.15 (m, 1 H), 2.28 (m, 3 H), 4.52 (s, 2 H) ), 4.74 (sextuplet, 1H), 5.63 (sa, 1H), 6.50 (d, 1H), 6.68 (d, 2H), 6.91 (t, 1H), 7.16 (t, 1H), 7.18 (d, 2H), 7.26-7.32 (m, 4H), 7.40 (br s, 2H). MS m / z: 473, 0 (M + 1). (+) -Cis - V-. { 2-methyl-l- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-40) (±) -Cis-N- was made. { 2-methyl-l- [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (+) - cis-N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N -phenyl-propionamide. (±) - Cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was dissolved in DMF ( 5 ml) at room temperature. Sodium hydride (60% in oil, 0.061 g) was added and the mixture was allowed to stir for 30 min. 4- (2-Chloroethyl) morpholine hydrochloride (0.143 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then 3 x was extracted with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane- 5/95 methanol / dichloromethane) yielding the product (200 mg). XH NMR (CDC13) d: 1.09 (d, 3H), 1.12 (m, 4H), 1.22 (s, 4H), 2.23 (m, 3H), 2.50 (s, 4H) ), 2.70 (m, 2H), 4.01 (t, 2H), 4.70 (sextuplet, 1H), 5.59 (sa, 1H), 6.49 (d, 1H), 6.64 (d, 2H), 6.89 (t, 1H), 7.13 (d, 2H), 7.23-7.36 (m, 7H). MS m / z: 528, 1 (M + 1). (+) -Cis-N- [1 - (4-carbamoylmethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-41) (±) - Cis-N- [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol in-4-yl] -N-phenyl-propionamide was made starting from (+) - cis-N- [1 - (-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide. (+) - Cis-N- [1- (4-hydroxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (0.120 g) was dissolved ) in DMF (5 ml) at room temperature. Sodium hydride (60% in oil, 0.70 g) was added and the mixture was allowed to stir for 30 min. 2-bromoacetamide (0.320 g) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then 3 x was extracted with ethyl acetate, dried over MgSO 4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane- 10/90 methanol / dichloromethane) yielding the product (20 mg, 15%).
¾ NMR (CDCl 3) d: 1.12 (d, 3H), 1.14 (t, 3H), 1.24 (t, 1H), 2.25 (m, 3H), 4.42 (s, 2H) ), 4.73 (sextuplet, 1H), 5.61 (sa, 1H), 5.79 (s, 1H), 6.49 (d, 2H), 6.70 (d, 2H), 6.92 (t, 1H), 7, 14-7, 39 (m, 8H). MS m / z: 472, 0 (M + 1).
(+) -Cis-N-. { l- [4- (2-Hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1,2,3,4-etrahydro-quinolin--yl} -N-tenyl-propionamide (A-42) It was made (±) - Ci s-N-. { 1 - [4 - (2-Hydroxy-2-methyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (+) - Cis- ethyl ester. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3, -dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -acetic Ethyl ester of (+) -Cis- acid was dissolved. { 4- [2-methyl-4 - (phenyl -pro-ionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenoxy} -acetic (0.170 g) in THF and cooled to 0 ° C. and added methylmagnesium bromide (sol, 3.0 M in diethyl ether, 0.5 ml) and the reaction was allowed to stir at 0 ° C for 30 min. The reaction was quenched with a saturated solution of ammonium chloride and diluted with ethyl acetate. The organic extracts were separated and washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 50/50 hexanes / ethyl acetate-75/25 hexanes ethyl acetate) to produce the product (132 mg, 80%). X H NMR (CDCl 3) 'd: 1.10 (d, 3 H), 1.14 (t, 3 H), 1.23 (t, 1H), 1.29 (s, 6H), 2.24 (m, 3H), 3.70 (s, 2H), 4.74 (sextuplet, 1H), 5.61 (sa, 1H), 6, 50 (d, 1H), 6.66 (d, 2H), 6.91 (t, 1H), 7.13 (t, 1H), 7.14 (d, 2H), 7.25 (d, 1H) ), 7.32 (d, 1H), 7.37 (sa, 4H). MS m / z: 487, 1 (M + 1). (±) -Cis-N- [1- (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide (A-43) (+) -Cis-N- [1- (4-dimethylcarbamoylmethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made from acid (±) -cis-. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2H-quinol ina-1-carbonyl] -phenoxy} -acetic Acid (±) -Cis- was dissolved. { 4- [2-Methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1 -carbonyl] -phenoxy} -acetic (0.146 g) in THF (2 ml) at room temperature. HOBt (0.063 g), EDCI (0.071 g) and dimethylamine (2.0 M solution in THF, 0.162 ml) were added together with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate and washed with 1 N NaOH, 1 N HC1 and brine. The organic extracts were dried over MgSO4, filtered and concentrated. The crude residue was purified by chromatography on silica gel (100% ethyl acetate) to yield the product (84 mg, 54%). X H NMR (CDC13) d: 1.10 (d, 3 H), 1.13 (t, 3 H), 1.22 (t, 1 H), 2.23 (m, 3 H), 2.94 (s, 3 H) ), 3.00 (s, 3H), 4.60 (s, 2H), 4.71 (sextuplet, 1H), 5.58 (sa, 1H), 6.49 (d, 1H), 6.70 (d, 2H), 6.89 (t, 1H), 7.13 (d, 1H), 7.24 (d, 2H), 7.30 (d, 1H), 7.37 (sa, 7 H) ). MS m / z: 500, 1 (+ l). (+) -Cis-N- [1- (3-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-45) '(±) - Cis-iV- [1- (3-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the General procedure A, substituting 2-furoyl chloride for 3-dimethylaminobenzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (300 MHz, CDC13) d: 1.11-1.24 (m, 7 H), 2.12-2.40 (m, 3H), 2.83 (s, 6H), 4.80 ( ddd, 1H), 5.59 (sa, 1H), 6.49 (d, 1H), 6.55-6.69 (m, 3H), 6.92 (dd, 1H), 7.00 (ddd , 1H), 7.15 (ddd, 1H), 7.23-7.34 (m, 3H), 7.35-7.44 (m, 3H).
MS m / z: 442 (M + 1). (±) -Cis-N- [1- (4-dimethylamino-benzoyl) -2-methyl-1,2,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-46) (±) -Cis-N- [1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure General A substituting 2-furoyl chloride for 4-dimethylaminobenzoyl chloride and propionyl chloride for acetyl chloride. XH RM (300 MHz, CDCl 3) d: 1, 09-1.28 (t ?, 7 H), 2.12-2.39 (m, 3H), 2.93 (s, 6H), 4.73 (ddd, 1H) , 5.61 (sa, 1H), 6.47 (d, 2H), 6.62 (d, 1H), 6.96 (dd, 1H), 7.12-7.20 (m, 3H), 7.26-7.36 (m, 3H), 7.38-7.46 (m, 3H). MS m / z: 442 (M + 1). (±) -Cis-N- [2-methyl-1- (pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin--yl] -N-phenyl-propionamide (A-47) manufactured (±) -Cis- [2-ethyl-1- (pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the general procedure A substituting 2-fluoride chloride per 3-pyridinyl chloride and propionyl chloride per acetyl chloride. XH NMR (300 MHz, CDC13) d: 1.08-1.32 (m, 7 H), 2.16-2.44 (m, 3H), 4.84 (ddd, 1H), 5.62 ( sa, 1H), 6.53 (d, 1H), 6.97 (dd, 1H), 7.11 (dd, 1H), 7.20-7.51 (m, 8H), 8.55 (dd) , 1H), 8, 68 (ss, 1H). MS m / z: 400 (M + 1). (±) -Cia-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -4-methoxy-N-phenyl-butyramide ( A-48) (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -4-methoxy- N-phenyl-bu-iramide following general procedure A substituting 2-fluoride chloride for 4-fluorobenzoyl chloride and acetyl chloride for 4-methoxy-butyryl chloride. 1 H NMR (300 MHz, CDCl 3) d: 1.08-1.20 (m, 4H), 1.86-2.02 (m, 2H), 2.21-2.41 (m, 3H), 3 , 26 (m, 3H), 3.28-3.44 (m, 2H), 4.76 (ddd, 1H), 5.64 (sa, 1H), 6.43 (d, 1H), 6, 83-6.96 (m, 3H), 7.17-7.34 (m, 5H), 7.36-7.51 (m, 4H). MS m / z: 461 (M + 1). (+) -Cis-2- (acetyl-methyl-amino) -N- [1- (4-fl-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-49) (±) -Cis-2- (acetyl-methyl-amino) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2, 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for (acetyl-methyl-amino) chloride. acetyl. XH NMR (300 MHz, CDC13) d: 1.10-1.18 (m, 4H), 2.13 (s, 3H), 2.27-2.43 (m, 1H), 3.14 (m , 3H), 3.77 (d, 1H), 4.03 (d, 1H), 4.76 (ddd, 1H), 5.55 (sa, 1H), 6.45 (d, 1H), 6 , 81-6.95 (m, 3H), 7.15-7.26 (m, 3H), 7.31-7.49 (m, 5H), 7.54 (d, 1H).
MS m / z = 474 (M + 1). [1- (3-Methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -phenylamide of (+) - cis-cyclohexanecarboxylic acid (A-54) It was made [ (1- (3-methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -phenylamide of (+) - cis-cyclohexanecarboxylic acid following general procedure A by substituting chloride of 2 -fluoride was made and acetyl chloride by cyclohexanecarbonyl chloride.
XH NMR (CDCl 3) d: 0.8 (8H, m), 1.5-1.8 (5H, m), 2.0-2.4 (3H, m), 3.7 (3H, d) , 4.8 (1H, m), 5, 6 (1H, d), 6.2-6.6 (2H, m), 6.6-7.5 (11H, m). MS m / z: 483 (M + 1). [1- (3-methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -cis-isoxazole-5-carboxylic acid (A -55) [(1-) (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -cis-isoxazole- 5-carboxylic following general procedure A substituting 2-furoyl chloride for was performed and acetyl chloride for isoxazole-5-carbonyl chloride. XH NMR (CDC13) d: 1.2 (3H, d), 1, 2 (1H, m), 2.4 (1H, m), 3.6 (3H, s), 4.9 (1H, m ), 5.8 (1H, m), 6.4 (1H, d), 6.7-7.7 (12H, m), 8.2 (1H, s), 8.4 (1H, m ). MS m / z: 468 (M + 1). (+) -Cis-N- [1- (furan-3-carbonyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-acetamide (A-56) (+) -Cis-N- [1- (furan-3-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure General A substituting 2-furoyl chloride for 3-furoyl chloride. X H NMR (CDCl 3) d: 1.1 (3 H, d), 1, 2 (1 H, m), 2.0 (3 H, s), 2.2 (1 H, m), 4.7 (1 H, m ), 5.5 (1H, m), 5.9 (1H, s), 6.9 (1H, d), 7.1 (2H, m) 7.2-7.4 (7H, m). MS m / z: 375 (M + 1). (±) -Cis-N- [1- (3-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-61) (±) - Cis-N- [1- (3-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure General A substituting 2-furoyl chloride for 3-fluorobenzoyl chloride. X H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.7 (1 H, m ), 5.6 (1H, m), 6.4 (1H, d), 6.8 (1H, d), 6.9-7.4 (11H, m). MS m / z: 403 (M + 1). (±) -Cis-N- [1- (3, -difluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-62) ) (±) - Cis-N- [1- (3,4-difluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was manufactured following general procedure A substituting 2-fluoride chloride for 3,4-difluorobenzoyl chloride. X H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.7 (1 H, m ), 5.6 (1H, m), 6.5 (1H, d), 6.8-7.0 (4H, d), 7.3-7.5 (7H, m). MS m / z: 421 (M + 1). (±) -Cis-N- [1- (benzo [b] thiophene-3-carbonyl) -2-methi1-1, 2, 3,4-tetrahydro-quinolin-4-yl] -IV-phenyl-acetamide ( A-63) (±) -Cis-N- [1- (benzo [b] thiophene-3-carbonyl) -2-methyl-1,4,3-tetrahydro-quinoline-4-yl] - N-phenyl acetamide following general procedure A substituting 2-furole chloride for benzo [b] thiophene-3-carbonyl chloride. ?? NMR (CDCl 3) d: 1.2 (3H, d), 1.3 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 4.9 (1H, m) , 5.7 (1H, m), 6.5 (1H, d), 6.8 (1H, m), 7.1-7.5 (10H, m), 7.8 (1H, d), 8.0 (1H, d). MS m / z: 442 (M + 2). (±) -Cis-lV- [1- (3,5-dimethyl-thiophene-2-carbonyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl- acetamide (A-64) (±) -Cis-N- [1- (3,5-dimethyl-thiophene-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4 was made -yl] -phenyl-acetamide following the general procedure A substituting 2-furoyl chloride for 3,5-dimethyl-t-iofen-2-carbonyl chloride. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 1.7 (3H, s), 2.0 (3H, d), 2.0 (1H, m ), 2.3 (3H, s), 4.7 (1H, m), 5.5 (1H, m), 6.2 (1H, s), 6.7 (1H, d), 7.0 (1H, t), 7, 1-7, 4 (7H, m). MS m / z: 419 (M + 1). (+) -Cis -N- [1- (3-fluoro-benzol1) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide (A-65) (±) -Cis-N- [1- (3-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide was made following the procedure General A substituting 2-furoyl chloride for 3-fluorobenzoyl chloride and acetyl chloride for isopropyl chloride. X H NMR (CDCl 3) d: 1.0-1.2 (10H, m), 2.3 (1H, m), 2.7 (1H, m), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, m), 6.8-7.6 (12H, m).
MS m / z: 431 (M + 1). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide (A-66) (±) - Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-isobutyramide was made following the procedure General A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for isopropyl chloride. 1 H NMR (CDCl 3) d: 1.0-1.2 (10H, m), 2.3 (1H, m), 2.6 (1H, m), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.8-7.0 (3H, m), 7.1-7.4 (9H, m). MS m / z: 431 (M + 1). (±) -Cis-N- [1- (2,4-dimethyl-thiazole-5-carbonyl) -2-methyl-1,2, 3,4-tetrahydro-quinolin-4-yl] -iV-phenyl- Acetamide (A-67) (+) - Cis-N- [1- (2,4-dimethyl-thiazole-5-carbonyl) -2-araethyl-1,2,3,4-tetrahydro-quinoline-4 was made -yl] -N-phenyl-acetamide following general procedure A substituting 2-furoyl chloride for 2,4-dimethyl-thiazole-5-carbonyl chloride. ¾ R (CDC13) d: 1.2 (3H, d), 1.2 (1H, m), 2.0 (3H, s), 2.2 (3H, s), 2.3 (1H, m), 2.6 (3H, s), 4.7 (1H, m), 5.4 (1H, m), 6.8 (1H , d), 7.1 (2H, m), 7.2-7.5 (6H, m). MS m / z: 420 (M + 1). (±) -Cis-N- [1- (furan-2 -carbonyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide (A-68) (±) -Cis-N- [1- (furan-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure General A substituting propionyl chloride for acetyl chloride. ?? NMR (CDCl 3) d: 1.0-1.2 (7H, m), 2.2-2.4 (3H, m), 4.7 (1H, m), 5.4 (1H, m), 6.2 (2H, m), 6.8 (1H, d), 7.0-7.4 (9H, m). MS m / z: 389 (M + 1). (+) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-butyramide (A-69) (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-butyramide was made following the procedure General A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for butyryl chloride. ¾ NMR (CDCl 3) d: 0.8 (3H, t), 1.2 (3H, d), 1.2 (1H, m), 1.5 (2H, m), 2.0 (3H, m ), 4.7 (1H, m), 5.4 (1H, m), 6.5 (1H, d), 6.6-6.8 (4H, m), 6.9-7.3 ( 8H, m). MS m / z: 432 (M + 2).
(±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -2-phenoxy-iV-phenyl-ace-amide (A-72) (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -2-phenoxy was manufactured -N-phenyl-acetamide following general procedure A substituting 2-furoyl chloride for de-fluorobenzoyl chloride and acetyl chloride for 1-chloro-3-phenoxy-propan-2-one. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.3 (1H, m), 4.5 (2H, s), 4.7 (1H, m ), 5.7 (1H, m), 6.4 (1H, d), 6.7-6.9 (7H, m), 7.1-7.4 (9H, m), 10.0 ( 1H, m). MS m / z: 496 (+2). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -3, -diphenyl-propionamide (A-73) ) (+) -Cis-N- [1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -3, N-diphenyl-propionamide was made following general procedure A substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-phenylpropionyl chloride. X H NMR (CDCl 3) d: 1.2 (3 H, d), 1.2 (1 H, m), 2.2 (1 H, m), 2.7 (2 H, t), 3.1 (2 H, t ), 4.7 (1H, m), 5.7 (1H, m), 6.6 (1H, d), 6.8-7.6 (17H, m). MS m / z: 494 (M + 2). (+) -Cis-N- [1- (benzo [b] thiophene-2-carbonyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide ( A-75) (±) -Cis-N- [1- (benzo [b] thiophene-2-carbonyl) -2-methyl-1,4,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for benzo [b] thiophene-2-carbonyl chloride and propionyl chloride for acetyl chloride.
XH NMR (CDClj) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, m) , 6.9 (1H, d), 7.0 (2H, m), 7.2-7.5 (9H, ra), 7.6 (1H, d), 7.8 (1H, d). MS m / z: 456 (M + 2). (±) -Cis-N- [1- (4-cyano-benzoyl) -2-methyl- 1, 2, 3, 4- tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-76) (+) -Cis-N- [1- (4-cyano-benzoyl) -2-methyl was manufactured -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl -pro-ionamide following general procedure A substituting 2-furoyl chloride for 4-cyanobenzoyl chloride and propionyl chloride for acetyl chloride. LH NMR (CDCl 3) d: 1.1-1.3 (7H, m), 2.2-2.4 (3H, m), 4.8 (1H, m), 5.6 (1H, m) , 6.4 (1H, d), 6.9 (1H, t), 7.2-7.6 (11H, m). MS m / z: 424 (M + 1). (±) -Cis-N- [1- (3-fluoro-4-methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide ( A-77) (±) -Cis-N- [1- (3-fluoro-4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-enyl-propionamide following general procedure A substituting 2-furoyl chloride for 3-fluoro-4-methoxybenzoyl chloride and propionyl chloride for acetyl chloride. XE NMR (CDCl 3) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 3.8 (3H, s), 4.8 (1H, m) , 5.6 (1H, m), 6.5 (1H, d), 6.7 (1H, t), 6.8 (1H, d), 6.9 (1H, t), 7.2- 7.5 (8H, ra). MS m / z: 447 (M + 1). (±) -Cis-N- [1- (4-methoxy-3-methyl-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-78) (±) - Cis-N- [1- (4-methoxy-3-methyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 3-methyl-4-methoxybenzoyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDC13) d: 0.9-1.1 (7H, m), 1.8-2.2 (6H, m), 3.8 (3H, s), 4.8 (1H, m) , 5.6 (1H, m), 6.5 (2H, m), 6.7-7.8 (10H, m). MS m / z: 443 (M + 1). (+) -Cis-N- [1- (4-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-79) (±) -Cis-N- [1- (4-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure General A substituting 2-furole chloride for 4-ethoxybenzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.1-1.3 (7H, m), 1.4 (3H, t), 2.2-2.4 (3H, m), 4.0 (2H, c), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.9 (2H, d) 6.9 (1H, t), 7.2-7.6 (9H, m). MS m / z: 443 (M + 1). (+) -Cis-N- [2-methyl-1- (4-trifluoromethyl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-80) (+) -Cis-N- [2-methyl-1- (4-trifluoromethyl-benzoyl) -1,2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-propionamide was made following the General procedure A substituting 2-furoyl chloride for 4-trifluoromethylbenzoyl chloride and propionyl chloride for acetyl chloride. 2 H NMR (CDCl 3) d: 1.1-1.3 (7H, m), 2.2-2.4 (3H, m), 4.8 (1H, m), 5.6 (1H, m) , 6.4 (1H, d), 6.9 (1H, t), 7.2-7.6 (11H, m). MS m / z: 319 (M-147).
(±) -Cis-N- [1- (4-benzylmorpholine-2-carbonyl) -2-methyl-1,4-, 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-81) (±) -Cis-N- [1- (4-benzyl-morpholine-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-benzyl-morpholine-2-carbonyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDC13) d: 1.1-1.2 (7H, m), 2.1-2.3 (4H, m), 2.6 (3H, m), 3.5 (2H, m) , 3.9 (1H, m), 4.2 (1H, m), 4.7 (1H, m), 5.2 (1H, m), 7.1-7.5 (14H, m) . S m / z: 498 (M + l). (±) -Cis-N- [1- (4-ethyl-morpholine-2-carbonyl) -2-methyl-1,2, 3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-82) (±) -Cis-N- [1- (4-Ethyl-morpholine-2-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-ethyl-morpholine-2-carbonyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.1-1.2 (10H, m), 2.1-2.4 (6H, m), 2.6 (2H, m), 3.6 (1H, t), 3.9 (1H, m), 4.2 (1H, m), 4.7 (1H, m), 5.2 (1H, m) , 7.2-7.5 (14 H, m). MS m / z: 436 (M + 1). (±) -Cis-N- [2-methyl-l- (4-phenoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-83) (±) -Cis-N- [2-methyl-1- (4-phenoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following the procedure General A substituting 2-furoyl chloride for 4-phenoxy benzoyl chloride and propionyl chloride for acetyl chloride.
?? NMR (CDCl 3) d: 1.0-1.2 (7? M), 2.2-2.4 (3? M), 4.7 (1? M), 5.6 (1H, ni), 6.5 (1H, d), 6.5 (1H, d), 6.8 (2H, d), 7.0-7.4 (15H, m). MS m / z: 491 (M + 1). (±) -Cis-N- [1- (4-fluoro-3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-84) (+) - C sN- [1- (4-fluoro-3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol in-4-yl] - N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-fluoro-3-methoxybenzoyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.0-1.2 (7H, m), 2.2-2.4 (3H, m), 3.6 (3H, s), 4.7 (1H, m) , 5.6 (1H, m), 6.4 (1H, d), 6.7-6.9 (4H, m), 7.1-7.4 (7H, m). MS m / z: 447 (M + 1). (+) -Cis-N- [1- (4-methoxy-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A- 85) (±) -Cis-N- [1- (4-methoxy-3-trifluoromethyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol in-4-yl] was manufactured -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 4-methoxy-3-trifluoromethylbenzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.0-1.2 (7H, m), 2.2-2.4 (3H, m), 3.8 (3H, s), 4.7 (1H, m) , 5.6 (1H, m), 6.5 (1H, d), 6.7 (1H, d), 7.0 (2H, m), 7.2-7.4 (7H, m), 7.8 (1H, s). MS m / z: 497 (M + 1). (±) -Cis-N- [1- (2,3-dihydro-benzofuran-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl- propionamide (A-86) (+) -Cis-N- [1- (2,3-dihydro-benzofuran-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-qumolin-4 was made -yl] -N-phenyl-propionamide following general procedure A substituting 2-furoyl chloride for 2-chloride, 3-dihydro-benzofuran-5-carbonyl and propionyl chloride by acetyl chloride. LK NMR (CDC13) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 4.5 (2H, t), 4.8 (1H, m) , 5.6 (1H, m), 6.5 (2H, m), 6.9 (2H, m), 7, 1-7.4 (7H, m). MS m / z: 441 (+ l). (+) -Cis-iV-. { 2-methyl-l- [4- (3-methyl-ureido) -benzoyl] -1,2,3,4-tetra idro-q inolin -il} -N-phenyl-acetamide (A-87) (±) - Cis-N- was made. { 2-methyl-1 - [4 - (3-met-ilido) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-acetamide from (±) - ci sN- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl acetamide. (±) -Cis-N- [1- (4-amino-benzoyl) -2-methyl-1,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was dissolved following the procedure A, substituting 2-furoyl chloride for 4-nitrobenzoyl chloride and propionyl chloride for acetyl chloride. The resulting nitro analog was reduced with Pd / C (10%) in ethanol on a Parr shaker at 241.316 kPa (35 psi). (±) - Ci sN- [1- (4-amino-benzoyl) -2-met-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was dissolved (150 mg , 0.376 mmol) in 10 mL of toluene and 64 mg of methyl isocyanate (1.13 mmol) were added thereto. The resulting reaction mixture was stirred at room temperature for 2 hours and then heated at 50 ° C overnight. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1:19), to give the title compound (87 mg, 51%). XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 2.7 (3H, s ), 4.7 (1H, m), 5.1 (2H, m), 5.6 (1H, m), 6.5 (1H, d), 6.9-7.0 (6H, m) , 7.2 (1H, t), 7.2-7.4 (5H, m). MS m / z: 457 (+ l). (+) -Cls -N- [1- (4-diethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-88) (±) -Cis-N- [1- (4-diethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made from of (+) - cis-N- [1- (4-amino-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide. (±) - Cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide was dissolved in methylene and ethyl iodide (1.5 equiv.) followed by K2C03 / The reaction was allowed to stir at room temperature for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1:19), to give the title compound. 1 H NMR (CDCl 3) d: 1.0-1.2 (10H, m), 2.0 (3H, s), 2.4 (1H, m), 3.3 (4H, c), 4.7 (1H, m), 5.6 (1H, m), 6.4 (2H, d), 6.6 (1H, d), 6.9 (1H, t), 7.0-7.4 ( 9H, m). MS m / z: 456 (M + 1). Acid (±) -cis-. { 4- [4- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2ff-quinoline-1-carbonyl] -phenylamino) -acetic acid (A-89) Acid (±) - cis- . { 4 - [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2/1-quinoline-1-carbonyl] -phenylamino} -acetic from (±) -cis-N- [1- (4-amino-benzoyl) -2-methyl-1, 2, 3, 4-etrahydro-quinolin-4-yl] -N-phenyl-acetamide . (+) -Cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was dissolved in dimethylformamide and ethyl ester of bromoacetic acid was added followed by K2C03. The reaction was allowed to warm to 90 ° C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (2:18), to give the ester. The ester was hydrolyzed using NaOH (aqueous) in methanol and water to give the title compound. 1 H NMR (CDC13) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 3.6 (1 H, s ), 4.7 (3H, a), 5.6 (1H, m), 6.3 (1H, m), 6.6 (1H, d), 6.8-7.4 (11H, m) . MS m / z: 458 (M + 1). (+) -Cis-. { N- [1- (4-methanesulfonylamino-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-90) (±) - Cis- { N- [1- (-methanesulfonylamino-benzoyl) -2-methyl-l, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide from (±) - cis-N- [1- (4-amino-benzoyl) -2-methyl-1, 2, 3, 4 -tetrahydro-quinol -inyl] -N-phenyl-acetamide. It was dissolved (+) - cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (50 mg , 0.12 mmol) in 5 ml DMF and methane sulphonic anhydride (21 mg, 0.12 mmol) was added. The resulting reaction mixture was heated to 45 ° C and stirred for 1 hour. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with methanol-dichloromethane (1: 9) to give the title compound (15 mg, 25%).
X H NMR (CDCl 3) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 3.0 (3H, s), 4.7 (1H, m) , 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1 (2H, m), 7.2- 7.4 (7H, m). MS m / z: 491 (M). (±) -Cis-N- [6-Fluoro-l- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-fluoro) phenyl) -propionamide (A-91) (+) - Cis-iV- [6-fluoro-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol was manufactured in-4-yl] -N- (4-fluoro-phenyl) -propionamide following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride, (±) -cis- (2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenylamine by (±) - cis- (6-fluoro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) - (4-fluoro-phenyl) -amine and propionyl chloride by acetyl chloride. It was synthesized. { ±) -Cis- (6-fluoro-2-methyl-1,2,3,4-tetrahydro-quinol -inyl) - (4-fluoro-phenyl) -amine following the reactions detailed in scheme 1, substituting aniline by 4-fluoroaniline. ? NMR (CDCl 3) d: 1.1-1.2 (6H, m), 2.2-2.4 (4H, m), 4.8 (1H, dd), 5.4-5.6 (1H , a), 6.4 (1H, dd), 6.6 (1H, td), 6.8-7.0 (2H, m), 7.0-7.4 (6H, m). MS m / z: 453 (M + 1). (+) -Cis-N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -iV- (4-bromo) phenyl) -propionamide (A-92) (±) - Cis-N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1,4,3-tetrahydro-quinoline was manufactured 4-yl] -N- (4-bromo-phenyl) -propionamide following the general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride, (±) - cis- (2-met il-1, 2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine by (±) - cis- (6-bromo-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) - (4-bromo-phenyl) -amine and propionyl chloride by acetyl chloride. (±) -cytos- (6-bromo-2-methyl-1,4,3,4-tetrahydro-quinol m-4-yl) - (4-bromo-phenyl) -amine was synthesized following the reactions detailed in Scheme 1, substituting aniline for -bromoaniline. XH NMR (CDC13) d: 1.1-1.2 (6H, m), 1.6 (1H, m), 2.2-2.4 (3H, m), 4.8 (1H, m), 5.4-5.6 (1H, a), 6.4 (1H, d), 6.8 (2H, ra), 7.0- 7.4 (6H, M), 7.8-7.9 (2H, m). MS m / z: 573 (M + 1). (±) -Cis-N- [1- (3-ethoxy-benzoyl) -2-methyl-l, 2,3, -tetrahydro-quinolin-4-yl] -N- phenyl-acetamide (A-93) manufactured (+) - Cis-N- [1 - (3-e-oxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 3-ethoxybenzoyl chloride. X H NMR (CDCl 3) d: 1.2 (3 H, m), 1.4 (4 H, m), 2.1 (3 H, s), 2.4 (1 H, m), 4.0 (2 H, m ), 4.9 (1H, m), 5.6 (1H, a), 6.6 (1H, d), 6.9 (2H, m), 7.0 (1H, m), 7.2 (1H, m), 7.3 (1H, m), 7.4-7.5 (7H, m). MS m / z: 429 (M + 1). (±) -Cis-N- [1- (4-isopropoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -IV-phenyl-propionamide (A-94) (±) -Cis-N- [1- (4-isopropoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure A, substituting 2-furoyl chloride for 4-isopropoxybenzole chloride and propionyl chloride for acetyl chloride.
¾ NMR (CDCl 3) d: 0.9-1.2 (12H, m), 1.4 (1H, m), 2.0 (3H, m), 4.3 (1H, m), 4.5 (1H, m), 5.4 (1H, a), 6.3 (1H, d), 6.4 (2H, d), 6.7 (1H, m), 6.9-7.2 ( 9H, m). MS m / z: 457 (M + 1). (±) -Cis-N- [1- (l-isopropyl-li-benzotriazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl- propionamide (A-95) (±) - Ci sN- [1 - (1-Isopropyl 1-lH-benzotriazole-5-carbonyl) -2-methyl-l, 2,3,4-tetrahydro-quinoline- 4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 1-isopropyl-β-benzotriazole-5-carbonyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.3 (7H, m), 1.8 (6H, m), 2.4 (3H, m), 5.0 (1H, m), 5.1 (1H, m ), 5.7 (1H, a), 6.6 (1H, d), 7.0 (1H, m), 7.2-7.5 (9H, m), 8.3 (1H, s). MS m / z: 482 (M + 1). (+) -Cis-N- [1- (3-Ethoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-96) (±) - Cis-N- [1- (3-ethoxy-benzoyl) -2-met i 1 - 1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the general procedure A, substituting 2-furoyl chloride for 3-ethoxybenzoyl chloride and propionyl chloride for acetyl chloride. H NMR (CDCl 3) 5: 1.2 (6H, m), 1.5 (4H, m), 2.4 (3H, m), 4.0 (2H, m), 4.9 (1H, m ), 5.7 (1H, a), 6.6 (1H, d), 6.8 (1H, d), 6.9 (1H, m), 7.1 (2H, m), 7.2 (1H, go.), 7.3-7.6 (7H, m). MS m / z: 443 (M + 1).
Ethyl ester of (+) - cis -4- acid. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2-yl-quinoline-1-carbonyl] -phenyl} -piperidine-l-carboxylic acid (A-97) Ethyl ester of (±) -Ci s-4 - was manufactured. { 4 - [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic following general procedure A, substituting 2-furoyl chloride for 4 - (4-chlorocarbonyl-phenyl) -piperidine-l-carboxylic acid ethyl ester and propionyl chloride for acetyl chloride. XH NMR (CDC13) d: 1.1-1.3 (10H, m), 1.5 (2H, m), 1.7 (2H, m), 2.3 (3H, m), 2.6 (1H, m), 2.8 (2H, t), 4.1 (2H, m), 4.2 (2H, m), 4.8 (1H, m), 5.6 (1H, a) , 6.5 (1H, d), 6.9 (1H, m), 7.2 (2H, m), 7.3-7.4 (9H, m). MS m / z: 554 (M + 1). (±) -Cis-N- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-98) (±) -Cis-N- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1,2,4,4-tetrahydro-quinolin-4-yl] - I \ 7-phenyl-propionamide from ethyl ester of (+) - cis-4- acid. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2-yl-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid. Ethyl ester of (±) - ci s-4 - was dissolved. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2H-quinoline-1-carbonyl] -phenyl} -piperidine-1-carboxylic acid (96 mg, 0.17 mmol) in acetonitrile (2 mL). Yodotrimethylsilane (74 μm, 0.51 mmol) was added and the reaction was allowed to stir at room temperature overnight. The excess reagent was quenched by the addition of methanol (1 mL) and the mixture was concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The extracts were washed with 1 M sodium hydroxide, saturated aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (3: 1 methylene chloride / methanol) (77). mg, 94%). XH NMR (CDC13) d: 1.1 (6H, m), 1.3 (1H, t), 1.6 (2H, m), 1.7 (2H, d), 2.3 (3H, m ), 2.6 (1H, m), 2.7 (2H, t), 3.2 (2H, d), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.2 (3H, m), 7.3-7.4 (6H, m). MS m / z: 482 (M + 1). (±) -Cis-N- [1- (4-Bromo-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide (A-99) (+) -Cis-N- [1- (4-bromo-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure A, substituting 2-furoyl chloride for 4-bromobenzoyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.2 (6H, m), 1.25 (1H, m), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a ), 6.4 (1H, d), 6.9 (1H, m), 7.1 (2H, d), 7.2 (1H, m), 7.3-7.4 (8H, m) . MS m / z: 477 (M + 1). (±) -Cis-N-. { 1- [4- (l-Acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-100) To a solution of (±) - cis- (2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -phenyl-amine (636 mg, 2.70 mol) in dichloromethane (10 ml) at room temperature was added diisopropylethylamine (1.04 g, 1.44 ml, 2.98 mmol) followed by tert-butyl ester of 4 - (4-chlorocarbonyl-phenyl) ) -piperidine-l-carboxylic acid prepared recently (2.98 mmol). The mixture was stirred at room temperature overnight, poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 70/30 hexanes: ethyl acetate) to yield pure amide (827 mg, 58%). The tert-butyl ester of (±) - cis-4 - [4 - (2-methyl-4-phenylamino-3,4-dihydro-2H-quinoline-1-carbonyl) -phenyl] -piperidine-l- carboxylic acid (827 mg, 1.57 mmol) formed in this manner was dissolved in methylene chloride (50 ml). Trifluoroacetic acid (3 mL) was added and the mixture was stirred at 70 min. The solvent and excess acid were removed under reduced pressure. The crude residue was dissolved in ethyl acetate and neutralized with 1 M sodium hydroxide (at pH = 10).,5) . The aqueous phase was extracted twice with more ethyl acetate. The extracts were combined and washed with brine, dried over sodium sulfate, filtered and concentrated to yield the crude diamine (676 mg, 100%) as an oil. To a solution of the piperidinamine obtained above (676 mg, 1.59 mmol) in methylene chloride (25 mL) was added diisopropylethylamine (616 mg, 849 μL, 4.77 mmol), followed by acetyl chloride (162 mg, 156 μ ?, 2.06 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with more methylene chloride. The extracts were combined, washed with brine, dried over sodium sulfate, filtered, dried and concentrated to yield the piperidinacetamide (844 mg, >; 100%). The crude piperidinacetamide obtained above (844 mg) was dissolved in methylene chloride (25 ml), to which was then added diisopropylethylamine (205 mg, 283 μl, 1.59 mmol) followed by propionyl chloride (4.42 g). g, 4.2 ml, 47.7 mmol). The resulting reaction mixture was stirred at room temperature for 96 h and concentrated. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The extracts were washed with brine and dried over sodium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient 50/50 ethyl acetate / hexanes to 100% ethyl acetate) yielding the product (437 mg, 52%). It separated (±) - Cis-N-. { 1- [4 - (1-acetyl-piperidin-4-yl) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - y. { 2S, 4i¾) - cis-N-. { 1- [4 - (1-acetyl-piperidin-4-yl) -benzoyl] -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-51 and A-50, respectively). XH NMR (CDC13) d: 1.2 (7H, m), 1.6 (2H, m), 1.8 (2H, d), 2.1 (3H, s), 2.3 (3H, m ), 2.6 (2H, m), 3.1 (1H, t), 3.9 (1H, m), 4.8 (2H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.1 (2H, d), 7.2-7.4 (7H, m). MS m / z: 524 (M + 1) (±) -Cis-N-. { l- [4- (l-Ethyl-piperidin-4-yl) -benzoyl] -2-methyl- 1, 2, 3, 4-tetra idro-quinolin-4-yl} -IV-phenyl-propionamide (A-101) (±) - Cis-N- was made. { 1 - [4 - (1-Ethyl-piperidin-4-yl) -benzoyl] -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (+) - cis-N- [2-methyl-1- (4-piperidin-4-1-benzoyl) -1,2,3,4-tetrahydro-quinolin-4- il] -N-phenyl-propionamide. (±) - Cis-N- [2-methyl-1- (4-piperidin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinolm-4-yl] -N-phenyl propionamide was dissolved in dichloromethane (3 ml). Acetaldehyde (18 μ?, 0.33 mmol) was added in a unit portion. The mixture was stirred at room temperature for 30 minutes and then a solution of sodium triacetoxyborohydride (35 mg, 0.165 mmol) in dichloromethane (1 mL) was slowly added, followed by 1 drop of acetic acid. The mixture was allowed to stir at room temperature overnight and was quenched with aqueous sodium bicarbonate. The biphasic mixture was extracted three times with methylene chloride (20 ml); The combined extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by HPLC to produce the product (35 mg, 62%). XH NMR (CDC13) d: 1.0-1.2 (9H, m), 1.3 (1H, m), 1.8 (4H, a), 2.0 (2H, m), 2.3 (3H, m), 2.5 (2H, m), 3.1 (3H, m), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d) , 6.9 (1H, m), 7.0 (2H, d), 7.1-7.4 (9H, m). MS m / z: 511 (M + 2). (±) -Cis-N- [2-methyl -1- (4-nitro-benzoyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide (A-102) (±) -Cis-N- [2-methyl-1- (4-nitro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the procedure A, substituting 2-furoyl chloride for 4-nitrobenzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.2 (7H, m), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a), 6.4 (1H, d) ), 6.9 (1H, m), 7.2-7.4 (9H, m), 8.0 (2H, d). MS m / z: 444 (M + 1). (+) -Cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-pro-ionamide (A- 103) (+) -Cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -IV-phenyl-propionamide was prepared from (±) -cis-N- [2-methyl-methyl-1- (4-nitro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. (±) -Cis-N- [2-methyl-1- (4-nitro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (200 mg , 0.45 mmol) in ethanol (20 ml). Palladium on carbon (10%) was carefully added and the resulting suspension was stirred under an atmosphere of hydrogen gas (275)., 790 kPa (40 psi)) overnight. The suspension was filtered through Celite® to remove the solids and the filter cake was washed three times with ethanol. The concentration of the solution produced the pure product (160 mg, 86%). X H NMR (CDCl 3) d: 1.2 (7 H, m), 2.3 (3 H, m), 3.9 (2 H, a), 4.7 (1 H, m), 5.6 (1 H, a ), 6.4 (2H, d), 6.6 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.1 (1H, m), 7.2 -7.4 (6H, m). MS m / z: 414 (M + 1). (±) -Cis-N- [2-methyl-1- (4-pyrrol-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-104) (±) -Cis-N- [2-methyl-1- (4-pyrrol-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-pyrrol-1-yl-benzole chloride and propionyl chloride for acetyl chloride. ? NMR (CDC13) d: 1.2 (6H, m), 1.3 (1H, m), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a) , 6.3 (2H, s), 6.6 (1H, d), 6.9 (1H, m), 7.1 (2H, s), 7.2-7.4 (llH, m). MS m / z: 464 (+ l). (+) -Cis-N- [1- (4-acetylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-105) (±) -Cis-N- [1- (4-acetylamino-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared from (±) -cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. To a solution of (±) -cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -JV-phenyl-propionamide ( 100 mg, 0.24 mmol) in 2.5 ml of tetrahydrofuran was added acetyl chloride (44 μl, 0.63 mmol) followed by triethylamine (88 μl, 0.63 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane-ethyl acetate (3: 1), to give the title compound (51 mg, 46%). X H NMR (CDCl 3) d: 1.1 (7H, m), 2.2 (3H, s), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a ), 6.5 (1H, d), 6.9 (1H, m), 7.1 (2H, d), 7.2 (1H, d), 7.3-7.4 (8H, m) , 8.4 (1H, a). MS m / z: 456 (M + l) Ethyl ester of (±) -cis- acid. { 4- [2-methyl-4- (phenyl-propionyl-amino) -3,4-dihydro-2J-quinoline-1-carbonyl] -phenyl} -carbamic (A-106) Ethyl ester of (+) - cis- acid was made. { 4 - [2-methyl-4 - (phenyl-propionyl-amino) -3,4-dihydro-2-f-quinoline-1-carbonyl] -phenyl} - Carbamic was manufactured from (±) -cis-N- [1- (4-amino-benzoi 1) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide, following the procedure described above in the synthesis of (+) - cis-N- [1- (4-acetylamino-benzoyl-1) -2-methyl-1,2,3,4-tetrahydro-quinoline-4 - il] -N-phenyl-propionamide, substituting acetyl chloride for ethyl chloroformate. ¾ NMR (CDC13) d: 1.1 (6 H, m), 1.3 (4 H, m), 2.3 (3 H, m), 4.2 (2 H, m), 4.8 ( 1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.7 (1H, a), 6.9 (1H, m), 7.1-7.4 (10H , m). MS m / z: 486 (M + 1). (±) -Cis -N-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-107) (±) - Cí-N- was made. { 2-methyl-1- [4 - (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinol-ir.-4-yl} -N-phenyl-propionamide from (±) - cis-N- [1- (4-bromo-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N - feni 1 -propionamide. Combine (+) - Cis-N- [1- (4-bromo-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (100 mg , 0.22 mmol) with cesium carbonate (355 mg, 1.09 ramol), racemic BINAP (25 mg, 0.04 mmol), Pd2dba3 (36 mmol, 0.04 mmol) and 1-methylpiperazine and was dissolved in toluene (10 ml). The reaction mixture was heated to 100 ° C in an argon atmosphere overnight. The reaction was cooled to room temperature, filtered and the solids washed with ether. The filtrate was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by HPLC. H NMR (CDCI3) d: 1, 2 (6 H, m), 1.3 (1 H, m), 2.2 (3 H, m), 2.3 (3 H, s), 2.5 (4 H, m), 3.2 ( 4H, m), 4.7 (1H, m), 5.6 (1H, sa), 6.6 (1H, d), 6.7 (2H, d), 7.0 (1H, m), 7.2-7.4 (9H, m). MS m / z: 498 (M + 2) (+) -Cis-N- [2-methyl-1- (4-pyrimidin-2-yl-benzoyl) -1,2,3,4-tetrahydro-quinoline- 4-yl] -N-phenyl-propionamide (A-108) (±) -Cis-N- [2-methyl-1- (4-pyrimidin-2-yl-benzoyl) -1,2,3, 4-tetrahydro-quinoline-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-pyrimidin-2-yl-benzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.2 (7H, m), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.2-7.4 (10H, m), 8.3 (2H, d), 8 , 8 (2H, d). MS m / z: · 478 (M + 2). (±) -Cis-N- [2-nthyl-l- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl) -1, 2, 3, 4-tetrahydro -quinolin-4-yl] -N-phenyl-propionamide (A-109) (±) -Cis-N- [2-methyl-1- (4-methyl-3,4-dihydro-2H-benzo [ 1,4] oxazine-7-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-chloride methyl-3, 4-dihydro-2H-benzo [1,4] oxazine-7-carbonyl and propionyl chloride per acetyl chloride. X H NMR (CDCl 3) d: 1.1 (6H, m), 1.3 (1H, t), 2.3 (3H, m), 2.8 (3H, s), 3.3 (2H, t ), 4.2 (2H, t), 4.7 (1H, m), 5.6 (1H, a), 6.3 (1H, d), 6.5 (1H, d), 6.6 (1H, d), 6.9 (1H, s), 7.0 (1H, m), 7.1 (1H, m), 7.3-7.4 (7H, m). MS m / z: 471 (M + 2). (±) -Cis-N- [2-Methyl-l- (4-morpholin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-110) (±) -Cis-N- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1,2,4,4-tetrahydro-quinolin-4-yl] - iV-phenyl-propionamide from (±) - cis-N- [1- (4-bromo-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide, following the procedure used to manufacture (±) -cis-N-. { 2-methyl-1- [4- (4-methyl-piperazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide substituting 1-methylpiperazine for morpholine. (+) -Cis-N- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1,2,4,4-tetrahydro-quinolin-4-yl] -N-phenyl- was removed propionamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - and (2S, 4R) - cis-N- [2-methyl-1 - (4-morpholin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-propionamide (A-120 and A-119, respectively). XH RN (CDC13) d: 1.1 (7H, m), 2.3 (3H, m), 3.1 (4H, t), 3.8 (4H, t), 4.7 (1H, m ), 5.6 (1H, a), 6.6 (1H, d), 6.7 (2H, d), 6.9 (1H, m), 7.2-7.4 (9H, m) . MS m / z: 485 (M + 2). (±) -Cis-N-. { 1- [4- (2, 5-dimethyl-pyrrol-1-yl) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N- phenyl-propionamide (A-111). (±) - Cis-N- was prepared. { 1- [4- (2, 5-dimethyl-pyrrol-1-yl) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (±) -cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol in-il] -N - phenyl-propionamide. A solution of (±) -cis-N- [1- (-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (150 mg , 0.36 mmol) and propionic acid (0.5 ml) in dry benzene (20 ml) was heated to reflux in an argon atmosphere in a flask equipped with a Dean-Stark trap while stirring with the exclusion of light. . The resulting solution was cooled to room temperature and concentrated in vacuo. The recovered oil was purified by chromatography on silica gel, eluting with hexane-ethyl acetate (3: 1) to give the title compound (140 mg, 80%). 1 H NMR (CDC13) d: 1.2 (7H, m), 2.0 (6H, s), 2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, a ), 5.9 (2H, s), 6.5 (1H, d), 6.9 (1H, m), 7.0 (1H, d), 7.2 (2H, m), 7.3 -7.4 (8H, m). MS m / z: 493 (M + 2). (±) -Cis-N-. { 1- [4- (2-Ethyl-butylamino) -benzoyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-112) (±) - Cis-N- was prepared. { 1 - [4 - (2-ethyl-butylamino) -benzoyl] -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide from (±) - cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N - phenyl-propionamide. To a solution of (±) - ci sN- [1 - (4-amino-benzoyl) -2-methyl -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (75 mg, 0.145 mmol) in dichloromethane (3 mL) was added a portion of 2-ethylbutyraldehyde (26 μL, 0.2 mmol) in. The mixture was stirred at room temperature for 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) in 1 ml of DCM was added slowly. A drop of acetic acid was added and the reaction was allowed to stir at room temperature overnight.
The excess reagent is quenched by the addition of aqueous saturated sodium bicarbonate. The resulting mixture was extracted three times with 20 ml of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by HPLC to yield the title compound (60 mg, 83%). LH NMR (CDC13) d: 0.9 (6H, m), 1.2 (7H, m), 1.4 (5H, m), 2. 3 (3H, m), 3.0 (2H, d), 4.7 (1H, m), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d) ), 7.0 (1H, m), 7.1 (2H, d), 7, 2 (1H, m), 7.3-7.4 (6H, m). MS m / z: 499 (M + 2). (±) -Cis-N- [2-methyl-1- (4-propylamino-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-113) (±) - Cis-N- [2-methyl-1- (4-propylamino-benzoyl) -1,2,3,4-te rahydro-quinol in-4-i 1] -N-phenyl-propionamide was prepared from (±) - cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-propionamide using the reductive amination conditions described for the synthesis of (±) - cis-N-. { 1 - [4 - (2-Ethyl-butylamino) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide. 2-Ethylbutyraldehyde was replaced by propionaldehyde. The reaction was poorly selective producing approximately equivalent amounts of mono- and di-alkylated products (i.e., (±) - cy sN- [1- (4-dipropylamino-benzoyl) -2-methyl-1,3,3,4 - tetrahydro-quinolin-4 -yl] -N-phenylpropionamide, see below). 2 H NMR (CDCl 3) d: 1.0 (3 H, m), 1.1 (7 H, m), 1.6 (2 H, m), 2.3 (3 H, m), 3.0 (2 H, d ), 4.0 (1H, a), 4.7 (1H, ra), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d), 6.9 (1H, m), 7.06 (2H, d), 7.14 (1H, m), 7.3-7.4 (6H, m). MS m / z: 457 (M + 2). (+) -Cis-N- [1- (4-dipropylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-114) (±) -Cis-N- [1- (4-Dipropylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was prepared in the form of a by-product in the synthesis of (±) - cy sN- [2-methyl-1- (4-propylamino-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide described above. ?? NMR (CDCl 3) d: 1.0 (6H, t), 1.1 (6H, m), 1.4 (1H, m), 1.5 (4H, m), 2.3 (3H, m) , 3.2 (4H, t), 4.7 (1H, m), 5.6 (1H, a), 6.4 (2H, d), 6.7 (1H, d), 7.0 ( 1H, m), 7.1-7.2 (3H, m), 7.3-7.4 (6H, m). MS m / z: 499 (M + 2). (+) -Cis-N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -IV- phenyl-propionamide ( A-115) (+) - Cis-N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1,2,3,4-etrahydro-quinolin-4-yl] - N-Phenyl-propionamide from (±) - ci sN- [1- (4-bromo-benzoyl) -2-methyl-1,2,3,4-tetrahydroquinoline in- 4-yl] -N- phenyl-propionamide following the procedure used to manufacture (±) - ci sN-. { 2-methyl-1 - [4 - (4-methyl i 1 -perazin-1-yl) -benzoyl] -1,2,3,4-tetrahydro-quinol in-4-yl} -N-phenyl-propionamide is substituted by 1-methylpiperazine by pyrrolidine. ¾ NMR (CDCl 3) d: 1.1 (7H, m), 2.0 (4H, m), 2.3 (3H, m), 3.2 (4H, m), 4.7 (1H, m ), 5.6 (1H, a), 6.3 (2H, d), 6.6 (1H, d), 6.9 (1H, m), 7.1-7.4 (9H, m) . MS m / z: 468 [M + 1).
(+) -Cis-N- [2-methyl-1- (4 -ureido-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide (A-116) (±) - Cis-N- [2-methyl-1- (4-ureido-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made from (+) - cis-N- [1- (4-amino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide. A mixture of (±) -cis-N- [1- (4-amino-benzoyl) -2-methyl-1,4,3,4-tetrahydro-quinol in 4-i 1] -N-phenyl-propionamide (100 mg, 0.24 mmol) and trimethylsilyl isocyanate (120 μl, 30.72 mmol) in dry DMF (0.5 ml) was stirred at room temperature for 3 days and then concentrated under reduced pressure at 30 ° C. C to dryness. The residual syrup was stirred with ethyl acetate, to which 10 ml of ethyl acetate was added with 10 ml of water. The pH was adjusted to 3.0 with 3 N HC1 and the separated aqueous phase was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield the product (10 mg, yield 9%). XH RN (CDC13) d: 1.2 (7H, m), 2.3 (3H, m), 4.7 (1H, m), 5.1 (2H, a), 5.6 (1H, a ), 6.5 (1H, d), 6.9 (5H, m), 7.2 (7H, m), 7.9 (1H, a). MS m / z: 457 (M + 1). Methyl ester of the acid (+) - cis-2 -. { 4 - [4 - (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2-yl-quinoline-1-carbonyl] -phenylamino} -propionic (A-117) Methyl ester of the acid (±) - ci s- 2 - was prepared. { 4 - [4 - (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2-f-quinoline-1-carbonyl] -phenylamino} -propionic from (+) - ci sN- [1 - (4-amino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-propionamide . A mixture of (±) -cytos-N- [1- (4-amino-benzoyl) -2-methyl-1,3,4-tetrahydro-quinol-4-yl] -JV-phenyl-propionamide ( 210 mg, 0.53 mmol), potassium carbonate (123 mg, 0.89 mmol) and methyl 2-bromopropionate (70 μl, 0.63 mmol) in dry dimethylformamide (2 mL) was heated at 100 ° C for 6 h, then it was cooled to room temperature and stirred with 20 ml of water until all the salts dissolved. The aqueous phase was separated and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, eluting with (97: 3 methylene chloride / methanol) to yield the title compound (220 mg, 87%). XH N (CDC13) d: 1.2 (4H, m), 1.4 (3H, d), 2.0 (3H, s), 2. 3 (1H, a), 3.7 (3H, s), 4.1 (1H, m), 4.7 (1H, m), 5.6 (1H, a), 6.3 (2H, d) ), 6.6 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.3-7.4 (7H, ra). MS m / z: 487 (M + 2). (±) -Cis-2-. { 4- [4- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2-yl-quinoline-1-carbonyl] -phenylamino} -propionamide (A-118) was prepared (±) - i s-2 -. { 4 - [4 - (acetyl-phenyl-amino) -2-met i 1 -3, -dihydro-2-f-quinoline-1 -carbonyl] -phenylamino} -propionamide from (± j - cis-2 -. {4 - [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl) methyl ester ] -phenylamino.] -propionic acid (2 ml, 2.0 M) was added with (±) - ci s-2 -. {4 - [4 - (acetylphenyl) methyl ester). amino) -2-methyl-3, 4-dihydro-2H-quinoline-1 -carbonyl] -phenylamino] -propionic acid (180 mg, 0.37 mmol) and a residue amount of ammonium chloride; it was heated at 100 ° C for 6 h in a pressure reactor with good mixing.After cooling to 0 ° C, the resulting precipitate was filtered and washed with ice water and extracted with ether.The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure.The crude product was purified by HPLC to give the title compound (10 mg, 6%). ¾ RM (CDC13) d: 1.2 ( 4H, m), 1.5 (3H, d), 2.1 (3H, s), 2.3 (1H, a), 3, 8 (1H, s), 4.4 (2H, a), 4.7 (1H, m), 5.6 (2H, m), 6.3 (2H, m), 6.6 (2H, d) ), 7.0 (1H, m), 7.1 (2H, d), 7.2 (1H, m), 7.3-7.4 (5H, m). MS m / z: 471 (M + 1) (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-123) (±) - Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4- was made il] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3-methoxybenzoyl chloride. (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was removed by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - y. { 2S, 4R) - cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,4,2-tetrahydro-quinolin-4-yl] -V- phenyl-acetamide (A- 126 and A-127, respectively). ¾ NMR (CDCl 3) d: 1.15 (3H, d; overlap 1H, t), 2.05 (3H, s), 2.33 (1H, m), 3.60 (3H, s), 4 , 80 (1H, m), 5.65 (1H, m), 6.55 (1H, d), 6.75-6.85 (3H, complex), 6.95 (1H, t), 7, 15 (1H, t), 7.25 (1H, t), 7.25-7.55 (6H, m). MS m / z: 415 (M + 1).
(±) -Trans-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -IV-phenyl-acetamide (A-124) (±) -Trans-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure General A, substituting 2-furoyl chloride for was performed and cis- (2-ethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -phenyl-amine for trans- (2-ethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -phenyl-amine. (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl-propionamide (A- 128) (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for was performed and propionyl chloride for acetyl chloride. XH RN (CDC13) d: 1.15 (3H, d; overlap 3H, t, 1H, t), 2.20 (2H, c), 2.33 (1H, m), 3.65 (3H, s ), 4.80 (1H, m), 5.60 (1H, m), 6.55 (1H, d), 6.75-6.85 (3H, complex), 6.95 (1H, t) , 7.15 (1H, t), 7.20 (1H, t), 7.25-7.55 (6H, tn). MS m / z: 429 (M + 1). (±) -Cis-N- [6-chloro-l- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro) - phenyl) -acetamide (A-129) (±) - Cis-N- [6-chloro-1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline was made -4-yl] -N- (4-chloro-phenyl) -acetamide following the general procedure A, substituting 2-furoyl chloride for was performed and (±) -cis- (2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -phenyl-amine by (+) - cis- (6-chloro-2-methyl-1,2,3-tetrahydro-quinolin-4-yl) - (4-chloro phenyl) -amine. (±) - Cis- (6-chloro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) - (4-chloro-phenyl) -amine was synthesized following the reactions detailed in the scheme 1, substituting aniline for 4-chloroaniline. ¾ NMR (CDC13) d: 1.15 (3H, d; overlap 1H, t), 2.02 (3H, s), 2.35 (1H, m), 3.65 (3H, s), 4.80 (1H, m), 5.60 (1H, m) , 6.42 (1H, d), 6.65-6.95 (overlap 1H, d; 1H, dd; 1H, dd), 7.15 (1H, t), 7.20-7.30 (6H , m), 7.40 (1H, d). MS m / z: 484 (M + 1). (+) -Cis-N- [2-methyl-l- (1-methyl-lff-ironol-2 -carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N- phenyl- Acetamide (A-130) (±) -Cis-N- [2-methyl-1- (1-methyl-lH-pyrrole-2-carbonyl) -1,2,4,4-tetrahydro-quinoline-4 was made - il] -N-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 1-metyl-1-pyrrole-2-carbonyl chloride. ½ NMR (CDCI3) d: 1.12 (3H, d; overlap 1H, t), 2.00 (3H, s), 2.35 (1H, m), 3.80 (3H, s), 4, 70 (1H, m), 5.50 (1H, m), 5.80 (1H, d), 6.55 (1H, d), 6.80 (1H, d), 7.00 (1H, t ), 7, 20-7, 50 (6H, m). MS m / z: 388 (M + 1). (+) -Cis-N- [2-methyl-1- (2-methyl-pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-131) (±) - Cis-N- [2-methyl-1- (2-methyl-pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 2-methyl -isonicotinoyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.11-1.16 (3H, d; overlap 3H, ty 1H, t), 2.20-2.35 (overlap 2H, c; and 1H, m), 2.47 (3H, s), 4.80 (1H, m), 5.60 (1H, m), 6.48 (1H, d), 6.65 (1H, d), 6.85 (1H, t) , 7.10-7.40 (8H, m), 8.30 (1H, d).
MS m / z: 414 (M + 1). (+) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -3-methyl-iV-phenyl-butyramide ( A-132) (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -3-methyl- ZV-phenyl-butyramide following general procedure A, substituting 2-fluoride chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-methyl-butyryl chloride. XH NMR (CDC13) d: 0.90 (2 x 3H, d), 1.15 (3H, d; overlap 1H, t), 2.15 (1H, m), 2.20-2.35 (overlap 2H, m; 1H, m), 4.80 (1H, m), 5.65 (1H, m), 6.50 (1H, d), 6.90 (4H, complex), 7.20-7 , 60 (8H, m). MS m / z: 445 (M + 1). (+) -Cis-N- [2-methyl-1- (6-methyl-pyridine-3-carboni1) -1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide ( A-133) (±) -Cis-N- [2-methyl-1- (6-methyl-pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 6-methyl-nicotinoyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.11-1.16 (3H, d; overlap 3H, ty 1H, t), 2.20-2.40 (overlap 2H, c; and 1H, m), 2.49 (3H, s), 4.80 (1H, m), 5.60 (1H, m), 6.48 (1H, d), 6.80-7.00 (lH, d; 1H, t), 7.10-7.50 (9H, m), 8.60 (1H, d). MS m / z: 414 (M + 1). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -2 -morpholin-4-yl-W- phenyl-acetamide (A-134) (+) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - 2-morpholin-4-yl-N-phenyl-acetamide following general procedure A, substituting 2-fluoride chloride for 4-fluorobenzoyl chloride and acetyl chloride for morpholinoacetyl chloride. (+) -Cis-N- [1- (2,3-dihydro-benzo [1,4] dioxin-6-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl ] -N- phenyl-propionamide (A-135) (±) -Cis-N- [1- (2,3-dihydro-benzo [1,4] dioxin-6 -carbonyl) -2-methyl-1 was made , 2,3,4-etrahydro-quinolin-4-yl] -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for (+) - cis-2,3-dihydro-benzo [] chloride. 1, 4] dioxin-6-carbonyl and propionyl chloride by acetyl chloride. ¾ RM (CDC13) d: 1.10 (3H, d; overlap 3H, t; 1H, t), 2.10 (2H, q, 1H, m), 4.10 (2 x 2H, m), 4 , 70 (1H, m), 5.65 (1H, m), 6.50-6.60 (2 x 1H, d), 7.20-7.40 (7H, m). MS m / z: 457 (M + 1). (±) -Cis-N- [2-methyl-1- (5-trifluoromethyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-136) (+) -Cis-N- [2-methyl-1- (5-trifluoromethyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinol in-4-yl] was manufactured. -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5-trifluoromethyl-thiophene-2-carbonyl chloride and propionyl chloride for acetyl chloride. ½ NMR (CDCl 3) d: 1.10-1.15 (3H, d; overlap 3H, t; 1H, t), 2.15-2.35 (2H, q, 1H, m), 4.70 (1H, m), 5.55 (1H, m), 6.45 (1H, d), 6 , 85 (1H, d), 7.00-7.20 (overlap lH, d; 1H, t), 7.20-7.60 (7H, m). MS m / z: 473 (M + 1).
(±) -Cis-N- [2-methyl-1- (6-trifluoromethyl-1-pyridine-3-carbonyl) -1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-137) (±) -Cis-N- [2-methyl-1- (6-trifluoromethyl-pyridine-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 6-trifluoromethyl-nicotinoyl chloride and propionyl chloride for acetyl chloride. ? NMR (CDC13) d: 1.10 (3H, d; overlap 3H, t; 1H, t), 2.00-2.40 (2H, q, 1H, m), 4.80 (1H, m), 5.65 (1H, m), 6.40 (1H, d), 7.00 (1H, d), 7.20-7.50 (9H, m), 8.70 (1H). MS m / z: 468 (M + 1). (+) -Cis-N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-138) (+) -Cis-N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3-methyl-isoxazole-5-carbonyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.10 (overlap 3H, d; 3H, t; 1H, t), 2.10- 2.40 (overlap 3H, s; 2H, c; 1H, m), 4.80 (1H, m), 5.50 (1H, m), 6.80 (1H , d), 7.10 (1H, t), 7.20-7.50 (9H, m). MS m / z: 404 (M + 1). (±) -Cis-N- [2-methyl-l- (4-oxazol-5-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-139) (±) -Cis-N- [2-Methyl-1- (4-oxazol-5-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 4-oxazol-5-yl-benzole chloride and propionyl chloride for acetyl chloride. XH NMR (CDC13) d: 1.00-1.20 (overlap 3H, t; 3H, d; 1H, t), 2.20-2.40 (2H, c; 1H, m), 4.80 ( 1H, m), 5.65 (1H, m), 6.55 (1H, d), 6.90 (1H, t), 7.20-7.60 (12H, m), 7.90 (1H , s).
MS m / z: 466 (M + 1). (+) -Cis-N- [1- (benzo [c] isoxazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin--yl] -IV- phenyl-propionamide (A - 140) (±) - Cis-N- [1- (benzo [c] isoxazole-3-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -iV was made phenyl propionamide following general procedure A, substituting 2-furoyl chloride for benzo [c] isoxazole-3-carbonyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.14 (3 H, t); 1.23 (3H, d), 2.20 (2H, c), 2.40 (1H, ra), 4.80 (1H, m), 5.60 (1H, m), 6.60 (1H , d), 7.00 (3H, complex), 7.00-7.40 (8H, m), 7.55 (1H, d). MS m / z: 440 (M + 1). Methyl ester of (+) - Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-succinamic acid ester ( A-141) (±) -cis-N- [1- (4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] - methyl ester was manufactured N-phenyl-succinamic following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for 3-chlorocarbonyl-1-propionic acid methyl ester. (+) -Cis-N-. { 1- [5- (4-chloro-phenyl) -furan-2-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -iV- phenyl-propionamide (A-142) (+) -Cis-N- was made. { l- [5- (4-Chloro-phenyl) -furan-2-carbonyl] -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl} -N-tenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5- (4-chloro-phenyl) -furan-2-carbonyl chloride and propionyl chloride for acetyl chloride. XE NMR (CDC13) d: 1, 08-1, 36 (7H, m), 2.15-2.35 (3H, m), 4.72 (1H, c), 5.40-5.60 ( 1H, a), 6.53 (2H, d), 6.89 (1H, d), 7.04-7.09 (1H, m), 7.17-7.40 (10H, m). MS m / z: 499 (M + 1). (+) -Cis-N-. { l- [5- (2-Chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl] -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-143) (+) - Cis-N- was made. { 1 - [5 - (2-chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl] -2-methyl-l, 2,3, -tetrahydro-quinolin-4-yl} -N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5- (2-chloro-4-trifluoromethyl-phenyl) -furan-2-carbonyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1, 08-1, 36 (7H, m), 2.15-2.35 (3H, m), 4.72 (1H, c), 5.40-5.60 (1H, a), 6.78-6.87 (2H, m), 7.05-7.49 (11H, m). MS m / z: 567 (M + 1). (±) -Cis-iV-. { 2-methyl-l- [5- (4-nitro-phenyl) -furan-2-carbonyl] -1,2,3-tetrahydro-quinolin-4-yl} -IV-phenyl-propionamide (A-144) (±) -Cis-N- was made. { 2-methyl-1 - [5- (4-nitro-phenyl) -furan-2-carbonyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide propionamide following general procedure A, substituting 2-furoyl chloride for 5- (4-nitrophenyl) -furan-2-carbonyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1, 13-1, 22 (7H, m), 2.20-2.36 (3H, m), 4.70 (1H, c), 5.40-5.60 ( 1H, a), 6.70 (2H, d), 6.87 (1H, d), 7.03 (1H, t), 7.25-7.47 (8H, m), 8.15 (2H , d). MS m / z: 510 (M + 1). (+) -Cis-N- [2-methyl-1- (5-methyl-isoxazole-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide ( A-145) (±) -Cis-N- [2-methyl-1- (5-methyl-isoxazole-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 5-methyl-isoxazole-3-carbonyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1, 10-1, 27 (7H, m), 2.13-2.35 (6H, m), 4.78 (1H, c), 5.40-5.60 (1H, a), 6.84-6.86 (1H, d), 7.05 (1H, t), 7.22-7, 38 (7H, m). MS m / z: 404 (M + 1). (±) -Cis-N- [2-methyl-1- (2-methyl-thiophene-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide ( A-146) (+) -Cis-N- [2-methyl-1- (2-methyl-thiophene-3-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - N-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 2-methyl-thiophene-3-carbonyl chloride and propionyl chloride for acetyl chloride. 2 H NMR (CDCl 3) d: 1, 01-1,27 (7H, m), 2.13-2.39 (6H, m), 4.62-4.78 (1H, m), 5.40- 5.60 (1H, a), 6.31-6.45 (2H, m), 6.60-6.83 (2H, m), 7.02-7.38 (6H, m). MS m / z: 420 (M + 1). [1- (4-Fl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -cis-but-3-enoic acid ( A-147) [(1-) - (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -phenyl-amide of (±) -cis-but -3-enoic following general procedure A, substituting 2-furoyl chloride for 4-fluorobenzoyl chloride and acetyl chloride for but-3-eneyl chloride. XH NMR (CDC13) d: 0, 98-1, 17 (4H, m), 2.13-2.29 (1H, m), 2.98-3.15 (2H, m), 4.60- 4.78 (1H, m), 4.98-5.20 (2H, m), 5.40-5.60 (1H, m), 5.70-5.91 (1H, m), 6, 40 (1H, d), 6.75-7.46 (11H, m). MS m / z: 429 (M + 1). (±) -Cis-N-. { 1- [3- (4-fluoro-phenyl) - [1, 2, 4] oxadiazole-5-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide (A-148) (±) -Cis-N- was made. { 1- [3 - (4-Fluoro-phenyl) - [1,2,4] oxadiazol-5-carbonyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -? G-phenyl-propionamide following general procedure A, substituting 2-furoyl chloride for 3- (4-fluoro-phenyl) - [1, 2, 4] oxadiazol-5-carbonyl chloride and propionyl chloride for chloride of acetyl. XH NMR (CDCl 3) d: 1.14 (3H, t), 1.23-1.25 (4H, m), 2.17-2.39 (3H, m), 4.78-4.80 ( 1H, m), 5.40-5.60 (1H, a), 7.03-7.09 (3H, m), 7.10-7.22 (4H, m), 7.24-7, 40 (4H, m), 7.97-8.02 (2H, m). MS m / z: 485 (M + 1). (+) -Cis-N- (l-benzoyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-150) It was manufactured (±) - Cis-N- (l-benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-enyl-acetamide following the general procedure A, substituting 2-furo-1-chloro chloride for benzoyl chloride. 1 H NMR (CDCl 3) d: 1.14 (3 H, d), 1.58-1.69 (1 H, m), 2.03 (3 H, s), 2.22-2.37 (1 H, m) , 4.72-4.86 (1H, m), 5.62 (1H, sa), 6.49 (1H, d), 6.88 (1H, t), 7.13-7.46 (12H , m). MS m / z: 385 (M + 1). (+) -Cis-N- [1- (4-chloro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-151) (±) -Cis-N- [1- (4-chloro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure General A, substituting 2-furoyl chloride for 4-chlorobenzoyl chloride. X H NMR (CDCl 3) 5: 1.14 (3 H, d), 1.61 (1 H, s), 2.03 (3 H, s), 2.24-2.36 (1 H, m), 4.71 -4.83 (1H, m), 5.51-5.69 (1H, m), 6.48 (1H, d), 6.93 (1H, t), 7.12-7.28 (7H , m), 7.35-7.40 (4H, ra). MS m / z: 419 (M) (+) -Cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -N - phenyl-acetamide (A-152) '(±) -Cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl was manufactured ] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 4-methoxy-benzoyl chloride. X H NMR (CDCl 3) d: 1.12 (3 H, d), 1.65 (1 H, m), 2.03 (3 H, s), 2.24-2.37 (1 H, m), 3.74 (3H, s), 4.66-4.84 (1H, m), 5.53-5.70 (1H, m), 6.50-6.54 (1H, d), 6.68 (2H , d), 6.89-6.96 (1H, m), 7, 05-7, 55 (9H, m). MS m / z: 415 (M + 1). (+) -Cis-N- [2-methyl-l- (2-methyl-benzoyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide (A-153) (+) -Cis-N- [2-methyl-1- (2-methyl-benzoyl) -1,2,3-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the general procedure A, substituting 2-furoyl chloride for 2-toluoyl chloride. XH NMR (CDC13) d: 1.11 (3H, d), 1.60-1.64 (1H, m), 1.97 (3H, s), 2.03-2.3 (4H, ra), 4.77-4.89 (1H, m), 5.41-5.58 (1H, m), 6.38-6 , 44 (1H, m), 6.79 (1H, t), 6.91-7.14 (4H, m), 7.16-7.28 (4H, m), 7.28-7.41 (3H, m). MS m / z: 399 (M + 1). (+) -Cis-N- [1- (3,5-dimethyl-isoxazole-4-carbonyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- phenyl- acetamide (A-154) (±) - Cis-N- [1- (3,5-dimethyl-isoxazole-4-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- was made 4-yl] -N-phenyl-acetamide following general procedure A, substituting 2-furoyl chloride for 3,5-dimethyl-isoxazole-4-carbonyl chloride. ¾ NMR (CDCl 3) d: 1.13 (3H, d), 1.57-181 (3H, m), 1.96-2.03 (5H, m), 2.15-2.63 (3H, m), 4.66-4.81 (1H , m), 5.41-5.50 (1H, m), 6.12 (1H, d), 7.03-7.15 (1H, m), 7.24-7.48 (7H, m ). MS m / z: 404 (M + 1). (+) -Cis-N- [1- (isoxazole-5-carbonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-155) (±) -Cis-N- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure A, substituting 2-furoyl chloride for isoxazole-5-carbonyl chloride. (±) -Cis-N- [1- (isoxazoi-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was removed by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2J?, 4S) - y. { 2S, 4R) - cis-N- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-70) and A-71, respectively). XH NMR (CDC13) d: 1.12 (3H, d), 1.64 (1H, s), 1.96 (3H, s), 2.21-2.31 (1H, m), 4.63 -4.75 (1H, m), 5.34-5.44 (1H, s), 5.98 (1H, s), 6.70 (1H, d), 7.04 (1H, t), 7.21-7.35 (7H, m), 8, 04-8, 08 (1H, m). MS m / z: 376 (M + 1). (±) -Cis-N- (l-cyclohexanecarbonyl-2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl) -N-tenyl-acetamide (A-157) (+) - Cis-N- (l-cyclohexanecarbonyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -W-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for chloride of cyclohexanecarbonyl. XH NMR (CDCl 3) d: 0.97 (3H, d), 1.13-1.27 (3H, m), 1.31-1.47 (2H, m), 1.58-1.89 ( 7H, m), 1.99 (3H, s), 2.14-2.24 (1H, m), 2.62-2.71 (1H, m), 4.70-4.78 (1H, m), 5.24-5.29 (1H, m), 7.07-7.10 (1H, m), 7.21-7.24 (2H, m), 7.28-7.33 ( 2H, m), 7.34-7.42 (4H, m). MS m / z: 391 (M + 1). (±) -Cis-N- [2-methyl-l- (pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -W-phenyl-acetamide (A-158) (±) -Cis-N- [2-methyl-1- (pyridine-4-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for isonicotinoyl chloride. ¾ NMR (CDCl 3) d: 1.16 (3H, d), 2.04 (3H, s), 2.25-2.35 (1H, m), 4.75-4.83 (1H, m) , 5.56-5.67 (1H, m), 6.45-6.48 (1H, m), 6.92 (1H, t), 7.08 (2H, d), 7.19-7 , 27 (3H, m), 7.34-7.42 (4H, m), 8.49 (2H, d).
MS m / z: 386 (M + 1). (±) -Cis-N- [1- (2, 5-dimethyl-2-tf-pyrazole-3-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- Phenyl-acetamide (A-159) (±) -Cis-N- [1- (2, 5-dimethyl-2H-pyrazole-3-carbonyl) -2-methyl-l, 2,3,4-tetrahydro was manufactured -quinolin-4-yl] -iV-phenyl-acetamide following the general procedure A, substituting 2-furoyl chloride for 2,5-dimethyl-2-pyrazol-3-carbonyl chloride. ¾ NMR (CDC13) d: 1.14 (3H, d), 2.02 (3H, m), 2.07 (3H, m), 2.23-2.32 (2H, m), 4.68 -4.76 (1H, m), 5.50 (1H, s), 6.66 (1H, d), 7.04 (1H, t), 7.21-7.28 (4H, m), 7.34-7.48 (4H, m).
MS m / z: 404 (M + 1). (±) -Cis-N- [2-methyl-1- (pyridine-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-160) (±) - Cis-N- [2-methyl-1- (pyridine-2-carbonyl) -1,2,4,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure A, substituting 2-furoyl chloride for pyridine-2-carbonyl chloride. XH NMR (CDCl 3) d: 1.17 (3H, d), 1.93-2.03 (1H, m), 2.02 (3H, s), 2.32 (1H, sa), 4.78 -4.86 (1H, m), 5.60-5.61 (1H, m), 6.51 (1H, d), 6.86 (1H, t), 6.99 (1H, d), 7.14-7.50 (9H, m), 8, 53 (1H, d). MS m / z: 385 (M + 1). (±) -Cis-N- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-propionamide (A-161) (+) - Ci sN- [1 - (isoxazol-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was made following the general procedure A, substituting 2-furoyl chloride for isoxazole-5-carbonyl chloride.
¾ NMR (CDCl 3) d: 0.95-1.20 (5H, m), 2.10-2.30 (4H, m), 4, 69-4, 74 (1H, m), 5.30- 5.43 (1? M), 5.96 (1H, s), 6.75 (1H, d), 7.75 (1H, t), 7.25-7.38 (8H, m), 8.06 (1H, s). MS m / z: 390 (M + 1). Scheme 5 (+) -Cis-N- [1- (3-methoxy-benzenesulfonyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamide (A- 162) (±) - sN- [1- (3-methoxy-benzenesulfonyl) -2-methyl-1,2,3,4-tetrahydro-quinol in-4-yl] -N-phenyl-1-acetamide was synthesized using the general procedure A, substituting 2-furoyl chloride for 3-methoxy-benzenesulfonyl chloride. ?? NMR (CDCl 3) d: 1.4 (3H, d), 1.4 (1H, m), 1.9 (3H, s), 2.0 (1H, m), 3.6 (3H, s), 4.1 (1H, m), 6.4 (1H, m), 6.9-7.4 (12H, m), 7 , 7 (1H, d). MS m / z: 451 (M + 1). Scheme 6 (+) -Cis-N- [1- (3-Methoxy-benzyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (A-164) (±) - Cis-N- [1- (3-methoxy-benzyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetic acid amide was synthesized by dissolving ( ±) - cis- (2-methyl-1,2,3,4-tetrahydroquinol-4-yl) aniline in dimethylformamide and adding potassium carbonate (1.0-10.0 equiv.), And 1-bromomethyl-3 -methoxy-benzene (1.1-3.0 equiv.), catalytic potassium iodide and stirred at room temperature for 18 hours. The reaction mixture was filtered to remove the inorganic salts and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (5-20%). Then, the corresponding aniline was acylated as previously described in general procedure A, giving (±) - cis-N- [1- (3-methoxy-benzyl) -2-methyl -1,2,3,4- tetrahydro-quinolin-4-yl] -N-phenyl-acetamide. ¾ NMR (CDC13) d: 1.15 (3H, d; overlap 1H, t), 1.90 (lH, m; 2H, m), 2.00 (3H, s), 3.33 (1H, m ), 3.60 (3H, s), 4.30 (1H, m), 6.30 (1H, complex), 6.90 (1H, t), 6.90-7.40 (10H, m) . S m / z: 443 (M + 1). (+) -Cis-N- (1-Benzyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-165) It was manufactured (±) - Cis-N- (1-benzyl-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl) -N-phenyl-acetamide following the procedure describing the synthesis of A-164, substituting 1 -bromomethyl-3-methoxy-benzene for benzyl bromide. aH NMR (CDCl 3) d: 1.15 (3H, d; overlap 1H, t), 1.90 (,, t?; 2H, m), 2.00 (3H, s), 3.33 (1H , m), 4.30 (1H, m), 6.30 (1H, m), 6.70 (1H, t), 6.90-7.40 (11H, m).
MS m / z: 413 (M + 1). (+) -Cis-N- (1-Ethyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide (A-166) (+) - Cis-N- (1-Ethyl-2-methyl-1,2,3-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide following the procedure described in the synthesis of A-164, substituting 1-bromomethyl -3-methoxy-benzene for ethyl bromide. XH NMR (CDC13) d: 1.01 (3H, t), 1.15 (3H, d; overlap 1H, t), 1.40 (1H, m), 1.90-2.00 (3H overlap, s; 1H, m), 3.20 (1H, m), 3.40 (1H, c), 3.60 (1H, ra), 4.60 (1H, s), 6.20 (1H, ma ), 6.60-6.80 (2H, m), 7.00-7.50 (7H, m). MS m / z: 309 (M + 1). Methyl ester of (±) -Cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid (A-167) Methyl ester was made of (±) - Cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2-fy-quinolin-1-yl] -acetic acid following the procedure described in the synthesis of A-164 , substituting 1-bromomethyl-3-methoxy-benzene for bromo-acetic acid methyl ester. X H NMR (CDCl 3) d: 1.20 (3 H, d; overlap 1 H, t), 1.80 (lH, m, 2.00 (3H, s), 3.40 (1H, m), 3.70 (3H, s), 3.90 (2H, s), 4.50 (1H, m), 6.10 (1H, t), 6.20 (1H, d), 6.75 (1H, m), 6.90-7.10 (3H, complex), 7.20-7.50 (3H, m) MS m / z: 353 (M + 1) Acid (±) -Cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2J-quinolin-1-yl. ] -acetic (A-16 8) Acid (±) - Cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid was made from (±) - cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid methyl ester To a methyl ester solution of (+) - cis- [4 - (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -acetic acid was added 1.0 N aqueous sodium hydroxide and the mixture was concentrated and the aqueous mixture was acidified to pH 6.0 using hydrochloric acid (1 N) followed by extraction twice with ethyl acetate. his Sodium phosphate, filtered and concentrated, producing the desired product. LR NMR (CDC13) d: 1.20 (3H, d; overlap 1H, t), 1.80 (lH, m, 2.00 (3H, s), 3.40 (1H, m), 3.90 (2H, s), 4.50 (1H, m), 6.10 (1H, t), 6.20 (1H, d), 6.75 (1H, m), 6.90-7.10 ( 3H, m), 7.20-7.50 (3H, m) MS m / z: 339 (M + 1).
Scheme 7 (+) - cis- (Acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2-yl-quinoline-1-carboxylic acid (3-methoxy-phenyl) -amide (A-169) (+) - cis- (acetyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid (3-methoxy-phenyl) -amide was synthesized using general procedure A, substituting 2-fluoride chloride for 3-methoxyphenylisocyanate using the following procedure. To a solution of (±) - cis- (3-methoxy-phenyl) - (2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl) -methanone (0.1 g, , 42 mmol) in toluene was added 3-methoxyphenylisocyanate (0.056 ml, 0.4255 mmol) and the reaction mixture was heated at 90 ° C for 18 hours. The reaction was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (80% / 20%), yielding 38% of the desired product. XH NMR (CDC13) d: 1.1 (3H, d), 1, 2 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.8 (3H, s) ), 4.5 (1H, m), 5.4 (1H, m), 6.6 (1H, d), 6.8 (2H, m) 7.1-7.5 (11H, m). S m / z: 430 (M + l). Scheme 8 (+) -Cis-N- (l-alkyl / aroyl-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-alkyl / aroylsulfonamide Can be prepared (+) - cis - 1 - (2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -alkanone or (+) - cis- (2-methyl-4-phenylamino-3, 4-dihydro- 2-quinolin-1-yl) -a-yl-methanone from compound 1 using general procedure A, substituting acetyl chloride for the corresponding sulfonyl chloride. Scheme 9 (±) -Cis-1- [4- (alkyl-phenylamino) -2 -methyl -3, -dihydro-2'-quinolin-1-yl] -alkanone or (±) -Cis-l- [4- (alkyl-phenyl-amino) -2-methyl-3,4-dihydro-2-yl-quinolin-l- il] -aryl methanone. (+) -Cis-l- [4- (alkyl-phenyl-amino) -2-methyl-3, 4-dihydro-2H-quinolin-1-yl] -alkanone or (±) can be prepared. - cis-1 - [4 - (alkyl-phenyl-amino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] -aryl-methanone from compound 1 using general procedure A, substituting chloride of acetyl by the corresponding alkyl chloride and using the alkylation process in the synthesis of A-164. Representative examples of compound 35 are shown in the following table. Scheme 10 A-170 (+) -Cis-3-ethyl-l - [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -1-phenyl-urea ( A-170) (+) -Cis-3-ethyl-1- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - was synthesized 1-phenyl-urea using general procedure A, substituting acetyl chloride for ethyl isocyanate using the following procedure. A solution of (+) - cis- (3-methoxy-phenyl) - (2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl) -methanone in DMF was added isocyanate ethyl acetate and the reaction mixture was heated at 90 ° C for 18 hours. The reaction was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethyl acetate (5-20%). ¾ RN (CDC13) d: 1.05-1.20 (3H, t; overlap 3H, d; and 1H, t), 2.35 (1H, m), 3.30 (2H, c), 3, 67 (3H, s), 4.36 (1H, t), 4.80 (1H, m), 5.65 (1H, m), 6.50 (1H, d), 6.65 (1H, d) ), 6.80 (1H, d), 6.85 (2H, complex), 7.00 (1H, t), 7.18 (1H, t), 7, 35-7, 50 (6H, m) . MS m / z: 444 (M + 1).
The compounds A-163, A-171-A-232 can be prepared by the schemes indicated in Schemes 1-10 and by the following general procedures A and others described herein. Those skilled in the art will be able to recognize or ensure, using only conventional experimentation, many equivalents to the specific embodiments of the invention described herein.
Table 1: Compounds Derived from General Procedure A Scheme 11 NHCbz '' ¡J CH3 BF3OEt 11 (Only cis) Benzyl ester of (+) - cis- (2-methyl-1,2,3,4-tetrahydro-quinolinyl) -carbamic acid (11) Aniline (3.64 ml, 39.97 mmol, 1) was dissolved , 0 equiv.) In methylene chloride (100 ml), Na 2 SO 4 (2 g) was added and cooled to -25 ° C. To the solution was added acetaldehyde (2.23 ml, 39.97 mmol, 1.0 equiv.) And stirred for 1 h at -25 ° C. Sodium sulfate was removed by filtration and to the filtrate was added W-vinyl carbamic acid benzyl ester (7.07 g, 39.97 mmol, 1.0 equiv.) At -25 ° C, followed by ether diethylcolate. of boron trifluoride (0.50 ml, 3.9 mmol, 0.1 equiv.). The reaction was allowed to stir at -25 ° C for 1 h and then was warmed to room temperature and stirred for 10 h. The reaction was evaporated in vacuo and the residue was purified by an ultra-rapid Diotage system (20% ethyl acetate / 80% hexane), yielding 4.0 g, 33% benzylic acid ester (±) - ci s- (2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl) -carbamic acid as a white solid. X H NMR (300 MHz, CDC13) d: ..7.38 (m, 5H), 7.17 (d, 1H), 7.02 (t, 1H, C7-H), 6.68 (t, 1H ), 6.47 (d, 1H), 5.17 (sa, 2H), 5.07 (m, 1H), 4.92 (d, 1H), 3.57 (m, 1H), 2.30 (m, 1H), 1.47 (c, 1H), 1, 21 (d, 3H). General Procedure B Scheme 12 Benzyl ester of (±) -cis- [1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid ester (12) To a solution of (±) -cis- (2-Rethyl-1,2,3,4-tetrahydro-quinol-4-yl) -carbamic acid benzyl ester (500 mg, 1.68 mraol) in methylene chloride (20 ml) ) at room temperature was added diisopropylethylamine (542 mg, 749 μl, 4.2 mmol) followed by 4-dimethylaminobenzoyl chloride and was stirred at room temperature until no starting material remained. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq) and brine, dried over sodium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 70% hexanes / 30% ethyl acetate) to yield the amide (665 mg, 89%). ¾ NMR (300 MHz, CDC13) d: 1.24 (d, 3H), 1.36 (m, 1H), 2.75 (ddd, 1H), 2.91 (s, 6H), 4.79- 4.92 (m, 3H), 5.22 (s, 2H), 6.43 (d, 2?), 6.65 (d, 1?), 6.90 (dd, 1H), 7.07 -7.18 (m, 5H), 7.2-7.48 (m, 4H). MS m / z: 444 (M + 1). (+) -Cis-l- (4-dimeti-lamino-benzoyl) -2-methyl-1,2,3,4- 5-tetrahydro-4-aminoquinoline (13) (+) - cis- benzyl ester was dissolved [1- (- dimethyl-lamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid (665 mg, 1.49 mmol) in ethanol (30 mL). The The resulting solution was evacuated and refilled with argon. A catalytic amount of palladium on carbon (10%) was added. The vessel was evacuated again once and this time it was again filled with hydrogen from a balloon. Afterwards, the reaction was allowed to react at temperature 15 atmosphere overnight in a hydrogen atmosphere. The reaction was completed after 18 h. The mixture was carefully filtered and concentrated to a volume of 10%. The resulting concentrated solution was filtered through Acrodisc® and concentrated, yielding the crude amine (423 mg, 20 92%). LH NMR (300 MHz, CDC13) d: 1.19-1.40 (m, 4H), 2.76 (ddd, 1H), 2.95 (s, 6H), 4.08 (dd, 1H), 4.81 (m, 1H), 6.42 (d, 2H), 6.64 (d, 1H), 6.99 (dd, 1H), 7.08-7.23 (m, 5H), 7 , 52 (d, 1H). MS m / z: 310 (M + 1). 25 (±) -Cys-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-4- (iV-4-chlorophenyl) aminoquinoline (14) To a solution of (± ) - cis-1 - (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-4-aminoquinoline (423 mg, 1.36 mmol) in DMF (15 ml, dry) 4-chlorophenylboronic acid 30 (425 mg, 2.72 mmol), pyridine (322 mg, 330 μm, 4.08 mmol) and copper (II) acetate (494 mg, 2.72 mmol) were added. The heterogeneous green mixture was stirred open in the air for 1 h and then heated to 60 ° C and stirred overnight (14 h). Then, the mixture was cooled to rt and poured into rapidly stirred ethyl acetate (150 ml); the solids were removed by filtration. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (gradient of 100% hexanes to 50/50 hexanes / ethyl acetate) yielding the product aniline (120 mg, 22%) as a yellow oil. ¾ RN (300 MHz, CDCl3) d: 1.22 (d, 3H), 1.36 (ddd, 1H), 2.82 (ddd, 1H), 2.95 (s, 6H), 4.90 ( s ar 1H), 4.41 (day, 1H), 4.87 (ddd, 1H), 6.65 (d, 2H), 6.62-6.76 (m, 3H), 6.97-7 , 11 (m, 2H), 7, 17-7, 29 (m, 5H). MS m / z: 420 (M + 1) (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl- 1, 2, 3, 4- tetrahydro-quinolin-4-yl] -acetamide (15) To a solution of (+) - cis-1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-4 - (N-4-chlorophenyl) aminoquinolma (120 mg, 0.29 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (37 mg, 0.051 mL, 0.29 mmol) followed by acetyl chloride (2 mL). ). The mixture was stirred at 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. water and brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by chromatography on silica gel (gradient of 100% hexanes -25 / 75 hexanes / ethyl acetate) yielding (+) - cis-N- ( Pure 4-chloro-phenyl) -N- [1- (4-dimethylammo-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (45 mg, 34%) . XE NMR (300 MHz, CDC13) d: 1.14-1.33 (m, 4H), 2.13 (s, 3H), 2.24-2.39 (m, 1H), 2.94 (s, 6H), 4.75 (ddd, 1H), 5.61 (sa, 1H), 6.44 (d, 2H) ), 6.63 (d, 1H), 6.96 (dd, 1H), 7.07-7.36 (m, 6H), 7.40 (d, 2H). MS m / z: 420 (M + 1) (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N-tolyl-acetamide (Bl) (±) - cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4-i 1 was manufactured ] -N- o-tol i 1 -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for it was made and 4-chlorophenylboronic acid for 2-tol-ilboronic acid. ¾ NMR (CDC13) d: 1.14 (d, 3H), 1.26 (s, 1H), 1.58 (s, 3H), 1.97 (s, 3H), 2.08 (m, 1H ), 3.63 (s, 3H), 4.80 (sextuplet, 1H), 5.55 (s, 1H), 6.53 (d, 1H), 6.76 (s, 1H), 6.83 (t, 2H), 6.93 (t, 1H), 7.10 (t, 1H), 7.15-7.37 (m, 6H). MS m / z: 429 (M + 1) N- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2, 3, 4 -tetrahydro-quinolin-4-yl] -acetamide (B-2) (±) -Cis-N- (4-chloro-phenyl) -N- [1- (3-methoxy- benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride. Separated (±) - cis-N- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1,3-tetrahydro-quinolin-4-yl] -acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2J?, 4S) - and (2S, 4J¾) -cis-N- (4-chloro- phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (B-9 and B-8, respectively) 1H NMR (CDC13) d: 1.17 (d, 3H), 1.25 (t, 1H), 2.03 (s, 3H), 2.29 (m, 1H), 3.62 (s, 3H), 4.80 (sextuplet, 1H), 5.60 (sa, 1H), 6.54 (d, 1H), 6, 74 (s, 1H), 6.80 (t, 1H), 6.93 (t, 1H), 7.08 (t, 1H), 7.14-7.30 (m, 5H), 7.38 (d, 2H). MS m / z: 449 (M + 1) (±) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1 -. { thiophene-2-carbonyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (B-3) (+) - cis-N- (4-chloro-phenyl) -N- was manufactured [2-methyl-l- (thiophene-2-carbonyl) -1,2,4,4-tetrahydro-quinol-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 2-methyl chloride; -thiophenecarbonyl. (+) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinol in- 4 - il] -acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2 £, 4S) - and (2S, 4R) - cis-N- (4 - chloro-phenyl) -N- [2-methyl-1 - (thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-7 and B-6, respectively). ?? NMR (300 MHz, CDC13) d: 1.11-1.24 (m, 4H), 2.03 (s, 3H), 2.22-2.35 (m, 1H), 4.73 (ddd, 1H), 5.52 (sa, 1H), 6.69 (dd, 1H), 6.67 (dd, 1H), 6.89 (d, 1H), 7.08 (dd, 1H), 7, 21 (d, 2H), 7, 27-7, 43 (m, 5H). MS m / z: 425 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -iV- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-q-inolin- 4-yl] -isobu iramide (B-4) (±) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) was made -1,2,3, 4-te rahydro-quinol in-4-yl] -isobutyl amide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride and acetyl chloride for chloride of isobutyryl. Separated (±) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinol in-4-yl] -isobutyramide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2J¾, 4S) - y. { 2S, 4R) -cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1, 2, 3, 4-tetrahydro-quinoline- 4-yl] -isobutyramide (B-ll and B-10 respectively). XH NMR (CDC13) d: 1.13 (d, 6H), 1.16 (d, 3H), 1.25 (m, 1H), 2.23 (m, 3H), 2.39 (s, 1H), 2.60 (septuplet, 1H), 4.66 (sextuplet, 1H), 5.50 (sa, 1H), 6, 42 (s, 1H), 6.51 (s, 1H), 6.93 (d, 1H), 7.08 (t, 1H), 7.21 (d, 2H), 7.27 (d, 2H) ), 7.37 (S a, 2H). MS m / z: 468 (M + 1) (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- (4-fluoro-phenyl) -propionamide (B-5) It was manufactured (±) -cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4- tetrahydro-quinolin-4-yl] -N- (4-fluoro-phenyl) -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, 4-chlorophenylboronic acid for 4-fluorophenylboronic acid and propionyl chloride by acetyl chloride.
X H NMR (CDCl 3) d: 1.14 (t, 3 H), 1.15 (d, 3 H), 1.24 (m, 1 H), 2.26 (m, 3 H), 4.75 (sextuplet, 1 H) ), 5.61 (br s, 1H), 6.46 (d, 1H), 6.87 (m, 3H), 7.10-7.26 (m, 8H). MS m / z: 435 (M + 1) (±) -Cis-N- (4-chloro-3-methyl-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-q inolin-4-yl] -propionamide (B-12) (±) - cis-N- (4-chloro-3-methyl-phenyl) -N- [1- ( 4-fluoro-benzoyl) -2-met-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, of propionyl by acetyl chloride and 4-chlorophenylboronic acid by 4-chloro-3-tolylboronic acid. ¾ NMR (CDCl 3) d: 1.08 (t, 3H), 1.09 (d, 3H), 1.18 (m, 1H), 2.18 (m, 3H), 2.31 (s, 3H) ), 4.69! sextuplet, 1H), 5.49 (sa, 1H), 6.42 (d, 1H), 6.79 (t, 2H), 6.86 (t, 1H), 6.96 (dd, 1H), , 05-7, 22 (m, 6H). MS m / z: 465 (M + 1). (±) -Cis-N- [1- (4-Fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- (4-trifluoromethyl-phenyl) - propionamide (B-13) (±) - cis-N- [1- (4-fluoro-benzoyl) -2-met il-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-trifluoro- methyl-phenyl) -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, propionyl chloride for acetyl chloride and 4-chlorophenylboronic acid for 4-trifluoromethyl phenylboronic acid. ¾ NMR (CDCl 3) d: 1.15 (t, 3 H), 1.17 (d, 3 H), 1.20 (m, 1 H), 2.29 (m, 3 H), 4.79 (sextuplet, 1 H) ), 5.62 (sa, 1H), 6.49 (d, 1H), 6.87 (m, 3H), 7.19-7.28 (m, 6H), 7.41 (d, 1H) , 7, 69 (d, 1H). MS m / z: 485 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-14) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro was made -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride and propionyl chloride for acetyl chloride. Separated (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl-1) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - and (2S, 4i?) - cis-N- (4-chloro- phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -propionamide (B-18 and B-17, respectively). XH RM (CDC13) d: 1.14 (t, 3H), 1.15 (d, 3H), 1.25 (t, 1H), 2.29 (m, 3H), 3.74 (s, 3H ), 4.74 (sextuplet, 1H), 5.61 (sa, 1H), 6.53 (d, 1H), 6.68 (d, 2H), 6.93 (t, 1H), 7.14 -7.28 (m, 6H), 7.38 (d, 2H). MS m / z: 463 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,4,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-15) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro was made -quinolin-4-yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride.
Separated (±) - ci sN- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3-ehydro-quinolin-4-yl] - acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2i?, 4S) - and (2S, 4i?) -cis-N- (4-Chloro- phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-34 and B-35, respectively). 1 H NMR (CDC13) d: 1.14 (d, 3 H), 1.25 (t, 1 H), 2.04 (s, 3 H), 2.29 (m, 1 H), 3.74 (s, 3 H) ), 4.74 (sextuplet, 1H), 5.61 (sa, 1H), 6.53 (d, 1H), 6.68 (d, 2H), 6.93 (t, 1H), 7.14 -7.28 (m, 6H), 7.38 (d, 2H). MS m / z: 449 [M + l). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-16) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro was manufactured - quino1 in-4-yl] -propionamide from (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -propionamide. (+) - Cis-N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-propionamide was dissolved (0.548 g , 0.001 mol) in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added; the reaction was allowed to stir at room temperature for 4 h or until no starting material remained. The reaction was carefully washed with sat. NaHCO 3. and brine. The organic extracts were dried over gSO, filtered and concentrated. The phenol was concentrated and the residue was purified by flash chromatography Biotage using 100% EtOAc to give a white solid, yield 74%.
?? NMR (CDCl 3) d: 1.09 (d, 3?), 1.11 (t, 3?), 1.19 (m, 1?), 2.26 (m, 3H), 4.74 (sextuplete , 1H), 5.54 (sa, 1H), 6.46 (d, 1H), 6.53 (d, 1H), 6.96 (t, 1H), 7.14-7.40 (m, 9H).
MS m / z: 415 (M + 1). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-l, 2, 3, 4- tetrahydro-quinolin-4-yl] -2V-p-tolyl-propionamide (B-21) (±) -cis-N- [1- (4-fluoro-benzoyl) -2 was manufactured -methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-p-tolyl-propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, propionyl chloride for sodium chloride. acetyl and 4-chlorophenylboronic acid for 4-tolylboric acid. X H NMR (300 MHz, CDCl 3) d: 1.05-1.21 (m, 7 H), 2.11-2.54 (m, 6H), 4.73 (ddd, 1H), 5.56 ( sa, 1H), 6.37 d, 1H), 6.8-7.0 (m, 3H), 7, 1-7.4 (m, 8 H). MS m / z: 431 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-22) (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydrocarbonacetate was made -quinolin-4 -yl] -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride. (±) -cis-N- (4-chloro-phenyl) -jV- [1- (4-fluoro-benzoyl) -2-metyl-1, 2, 3, 4-ehydro-quinolin-4 - il] -acetamide was separated by chiral HPLC using a Chiralcel OD column and eluting with 95% hexane / isocratic 5% ethanol system, giving (2i?, 4S) - and (2S, 4i?) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide (B-26 and B- 27, respectively).
X H NMR (CDCl 3) d: 1.1 (d, 3 H), 1.1 (m, 1 H), 2.0 (d, 3 H), 2.3 (m, 1 H), 4.7 (m, 1 H), 5.6 (m, 1H), 6.5 (d, 1H), 6, 7-7.0 (m, 3H), 7.1-7.4 (m, 8 H). MS m / z: 436 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (B-24) (+) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-2-thiophene-2-carbonyl) -1,2,3,4-ehydro- quinoline in-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride. (±) -cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) - 1, 2, 3, 4-tetrahydro-quinoline was separated -4-yl] -acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2i?, 4S) - y (2 S, 4R) - cis-N - (4-Chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) - 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (B -28 and B-25, respectively). ¾ NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, d), 2.3 (1H, m), 2.4 (3H, s ), 4.7 (1H, m), 5.6 (1H, m), 6.4 (1H, m), 6.6 (1H, m), 7.0 (1H, m), 7.1 (1H, m), 7.2-7.4 (6H, m). MS m / z: 439 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1,2,3,4-tetrahydro-quinoline- 4 -yl] -propionamide (B-29) (±) -cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -1 was manufactured , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 5-methyl-2-thiophenecarbonyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.1-1.2 (7H, ra), 2.1-2.3 (3H, m), 2.3 (3H, s), 4.8 (1H, m) , 5.6 (1H, m), 6, .2-6.4 (2H, m), 6.8-7.4 (8H, m). MS m / z: 452 (+2). Ethyl ester of (±) -cytos-4- (4- { 4- [(4-chloro-phenyl) -propioni-1-amino] -2-methyl-3,4-dihydro-2H-quinoliiia -1- carbonyl.}. -phenoxy) -butyric acid (B-30). (+) - cis-4 - (4 -. {4 - [(4-chlorophenyl) -propioni-1-amino] ethyl ester was prepared] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -butyric from (±) -cis-N- (4-chloro-phenyl) -IV- [1- (4-Hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. (+) - cis-N- (4-chloro-phenyl) -N- [1- (-hydroxy-benzoyl-1) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] - was dissolved. propionamide (140 mg, 0.31 mmol) in DF (5 ml) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture was allowed to stir for 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (gradient of 80/20 hexanes / ethyl acetate-50/50 hexanes ethyl acetate) yielding the product (171 mg, 0.304 mmol, 98%). XH NMR (CDCl 3) d: 1.1-1.2 (7H, m), 1.3 (3H, t), 2.1 (2H, m), 2.3 (3H, m), 2.5 (2H, t), 3.9 (2H, t), 4.2 (2H, c), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d) , 6.7 (2H, d), 6.9 (1H, t), 7, 1-7, 3 (6H, m), 7.4 (2H, m). MS m / z: 563 (M + 1). (+) - cis-4- (4- { 4- [(4-Chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl acid} .-phenoxy) -butyric acid (B-31). (+) - cis-4 - (4 -. {4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -butyric acid from (+) - cis-4- (4-. {4- [(4-chloro-phenyl)] ethyl ester -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl, phenoxy) -butyric acid. Potassium carbonate (300 mg) was dissolved in water (5 ml) and (±) - cis-4 - (4 -. {4 - [(4-chloro-phenyl) -propionyl-amino) ethyl ester was added. ] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -butyric acid (171 mg, 0.303 mmol) dissolved in methanol (5 ml). The reaction was allowed to stir overnight at room temperature. The methanol was removed in vacuo and hydrochloric acid (1 N) was added until acid was made. Dichloromethane was added and 2 x was extracted; the combined extracts were dried over magnesium sulfate, filtered and concentrated, yielding the carboxylic acid (50 mg, 31%). XH NMR (CDC13) d: 1.1-1.2 (7H, m), 2.0 (2H, m), 2.3 (2H, m), 2.4 (3H, m), 3.3 (1H, s), 4.0 (2H, t), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d) 6.9 (1H, t), 7.1-7.3 (3H, m), 7.4-7.6 (5H, m). MS m / z: 535 (+ l). (±) -Cis-N- (4-chloro-phenyl) -N-. { 2-methyl-1- [4- (1 J-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide (B-32) (±) - cis-N- (4-chloro-phenyl) -N- was prepared. { 2-methyl-1- [4 - (lido-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -propionamide from (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinoline- 4-yl] -propionamide. (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoi-1) -2 -met-il-1,2,3,4-tetrahydro-quinoline-4 was dissolved - il] -propionamide (700 mg, 1.42 mmol) in DMF (10 mL) at room temperature. Sodium hydride (60% in oil, 227 mg, 5.68 mmol) was added and the mixture was allowed to stir for 30 min. Bromoacetonitrile (850 mg, 7.11 mmol) was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by chromatography on silica gel (30/70 ethyl acetate / dichloromethane) to yield the product (320 ng, 42%). The nitrile (140 mg, 0.25 mmol) was dissolved in toluene, sodium azide (160 mg, 2.5 mmol) and triethylammonium hydrochloride (345 mg, 2.5 mmol) were added and the mixture was heated to 80 ° C for one night. The reaction was cooled to room temperature and water was added, followed by hydrochloric acid (1N) until acidic. The aqueous solution was extracted three times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, dried and concentrated. The crude product was triturated with ethyl ether / hexanes, yielding a white solid (82 mg, 63%). X H NMR (CDCl 3) d: 1.0-1.2 (7H, m), 2.2-2.4 (3H, m), 4.8 (1H, m), 5.2 (2H, dd) , 5.6 (1H, m), 6.7 (2H, m), 6.9 (1H, t), 7.1 (2H, d), 7.2-7.6 (7H, m). MS m / z: 531 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-isobutoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-33) (±) - cis- (4-Chloro-phenyl) -N- [1- (4-i-sobutoxy-benzoyl-1) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-isobutyloxybenzoyl chloride.
XH NMR (CDC13) d: 0.9-1.0 (8H, m), 1.2 (3H, d), 2.0 (3H, s), 2.3 (1H, m), 3.6 (2H, d), 4.7 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.6 (2H, d), 6.9 (1H, m) , 7.1-7.4 (8H, m). MS m / z: 491 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -IV-. { 1 - [4- (3-Hydroxy-2, 2-dimethyl-propoxy) -benzoyl] -2-methyl-1, 2,3,4-tetrahydrochloridyl-4-yl} -acetamide (B-37) (±) - cis-N- (4-chloro-phenyl) -N- was prepared. { 1- [4 - (3-Hydroxy-2, 2-dimethyl-1-propoxy) -benzoyl] -2-met-l, 2, 2,3, 4-tetrahydro-quinolin-4-yl} -acetamide from (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2 -met-il-1,2,3,4-tetrahydro-quinoline -4-yl] -propionamide. It was dissolved (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl. ] -propionamide (210 mg, 0.484 mmol) in DMF (10 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimet i 1 -propan-1-ol (813 mg, 4.84 mmol), the reaction was heated to 95 ° C. C and stirred overnight. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (95/5 dichloromethane / ethyl acetate-70/30 dichloromethane / ethyl acetate) to yield the pure ester (110 mg, 44%). 'H NMR (CDCl 3) d: 1.0 (6H, s), 1.1 (3H, d), 1.1 (1H, m), 1.7 (1H, a), 2.0 (3H, s), 2.3 (1H, m), 3.5 (2H, s), 3.7 (2H, s), 4.8 (1H, m), 5.6 (1H, m), 6, 5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 521 (M + 1).
Methyl ester of (+) - cis -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-methyl ester carbonyl.}. -phenoxy) -2, 2-dimethyl-propionic acid (B-38). (+) - cis -3- (4- {4- [acetyl- (4-chloro- phenyl) -amino] -2-methyl-3,4-dihydro-2Ji-quinoline-1-carbonyl.] - phenoxy) -2,2-dimethyl-propionic from (+) - cis-N- (4 -chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide. (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl was dissolved ] -propionamide (400 mg, 0.92 mmol) in DF (25 ml) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propionic acid methyl ester (400 mg, 0.92 mmol), the reaction was heated to 95 ° C and It stirred for a night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (95/5 dichloromethane / ethyl acetate-70/30 dichloromethane / ethyl acetate) to yield the pure ester (40 mg, 8%). XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 1.3 (6H, s), 2.0 (3H, s), 2.3 (1H, m ), 3.7 (3H, s), 3.9 (2H, dd), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 549 (M + 1). (+) - cis- (4- {Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} phenyl) -acetic acid (B-39) (+) - cis- (4- {Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4} acid was made -tetrahydro-quinoline-4-yl] -amino.}.-phenyl) -acetic from (±) - cy sN- (4-cyanomethyl-phenyl) -N- 11 - (-methoxy-benzoyl) -2- methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide. (±) -cis-N- (4-cyanomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl was made ] -acetamid following general procedure B, substituting 4-dimethylaminobenzoyl chloride for -methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4- (phenylboronic acid) -acetonitrile. It was dissolved (+) - cis-N- (4-cyanomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl. ] -acetamide in ethanol (4 ml), potassium hydroxide (120 mg in 0.3 ml of water) was added and the reaction was heated at 80 ° C overnight. The ethanol was removed in vacuo and hydrochloric acid (1 N) was added until basic. Dichloromethane was added and 2 x was extracted; the combined extracts were dried over magnesium sulfate, filtered and concentrated, yielding the carboxylic acid (30 mg) after purification by HPLC. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.6 (2H, s) ), 3.8 (3H, s), 4.8 (1H, m), 5.7 (1H, m), 6.5 (1H, m), 6.6 (2H, m), 6.9 (1H, m), 7.1-7.3 (8H, m). MS m / z: 495 (M + 23). Acid (±) -cís-3-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid (B-40) (+) - cis- 3 - acid was manufactured. { acetyl - [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3, -te rahydro-quinolin-4-yl] -amino} -benzoic following the procedure for (+) - cis- (4. {acetyl - [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinoline-4-} il] -amino.}.-phenyl) -acetic, substituting 4- (phenyl boronic acid) -acetonitrile for 3-cyanophenylboronic acid.
The basic hydrolysis of the nitrile using 1 N NaOH in raetanol and water yielded the carboxylic acid and the primary amide, (±) -cis-3. { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzamide. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.8 (3H, s), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.6 (2H , d), 6.9 (2H, m), 7.1-7.5 (5H, m), 7.9-8.2 (2H, m). MS m / z: 481 (+23). (±) -Cis-3 -. { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-yl] -amino} -benzamide (B-41) XH NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.8 (3H, s), 4.8 (1H, m), 5.7 (1H, m), 6.5 (1H, m), 6.6 (2H, m), 6.9 (1H , m), 7.1-7.3 (4H, m), 7.4-7.6 (2H, m), 7, 7-7.8 (2H, m). MS m / z: 480 (M + 23). (±) -Cis-N- (4-Chloro-phenyl) -N- [1- (isoxazole-5-carbonyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] - propionamide (B-44) (±) -cis-N- (4-chloro-phenyl) -N- [1- (isoxazole-5-carbonyl) -2-methyl-1,2,3, 4- tetrahydro was manufactured -quinolin-4-yl] -propionamide following general procedure B, substing 4-dimethylaminobenzoyl chloride for 5-isoxazolocarbonyl chloride and propionyl chloride for acetyl chloride. lE NMR (CDCl3) d: 1.14 (3H, d; overlap 3H, ty 1H, t), 2.30 (overlap 2H, c; and 1H, m), 4.75 (1H, m), 5, 45 (1H, m), 6.00 (1H, d), 6.80 (1H, d), 7.10-7.40 (7H, m), 8.05 (1H, s). MS m / z: 424 (M + 1). (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (B-45) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-cyclopentyloxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro- quinol in-4-yl] -acetamide from (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoi-1) -2-methyl-1, 2 , 3,4-tetrahydro-quinol-4-yl] -propionamide. To a solution of (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3-tetrahydro-quinoline- 4 - il] -acetamide in dimethylformamide was added cyclopentyl bromide, potassium carbonate (3.0 equiv.) and potassium iodide (catalytic) and heated at 65 ° C overnight. The reaction mixture was filtered to remove the inorganic salts and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of ethyl acetate-methanol (2-20% methanol) XH NMR (CDC13) d: 1.15 (3H, d; overlap 1H, t ), 1.57 (2H, m), 1.79 (3 x 2H, m), 2.04 (3H, s), 2.30 (1H, m), 4.60-4.80 (1H, q, 1H, m), 5.60 (1H, m), 6.50 (1H, d), 6.62 (1H, d), 6.90 (1H, t), 7.10-7.30 (9H, m), 7.40 (1H, d). S m / z: 504 (M + 1). (+) -Cis-N-. { l- [4- (4-Acetyl-piperazin-1-yl) -benzoyl] -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide (B-46). (+) - ci sN- [1 - [4 - (4-Acetyl-piperazin-1-yl) -benzoyl] -2- methyl -1,2,3,4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide from (±) - ci sN- (4-chloro-phenyl) -IV- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2 , 3, -tetrahydro-quinolin-4-yl] -propionamide. It was dissolved (±) - Ci sN- (4-chloro-phenyl) -iV- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide (1.07 g, 2.39 mmol) er. pyridine (5 ml) and trifluoromethanesulfonic anhydride (703 [mu], 2.5 mmol) was added thereto. The reaction was stirred at room temperature for 3 h. The reaction was partitioned between ether and water and the aqueous product was extracted three times with ether. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude triflate was purified by chromatography on silica gel (gradient of 70/30 hexanes / ethyl acetate-40/60 hexanes / ethyl acetate) yielding (1.0 g, 74%) of the pure material. Triflate, Pd2 (dba) 3, BINAP, cesium carbonate and 18-crown-6-ether in toluene were added with IV-acetylpiperazine and the reaction mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient ethyl acetate-methanol (2-20%). XH NMR (CDC13) d: 1.13 (3H, d; overlap 1H, t), 2.02 (3H, s), 2.10 (3H, s), 2.35 (1H, m), 3.20 (2 x 2H, m), 3.60 (2H, t), 3.70 (2H, t), 4.80 (1H, m), 5.65 (1H, m), 6.55 (1H, d), 6.70 (1H, d), 6, 95 (1H, t), 7.10-7.40 (9H, m). MS m / z: 546 (M + 1). (+) -Cis-N- (3-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-q inolin-4-yl] -acetamide (B-50) (±) - cis-N- (3-chlorophenyl) -N- [1- (4-fluoro-benzoyl) -2 -met-il-1,2,3,4 was manufactured - tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for -fluorobenzoyl chloride and 4-chlorophenylboronic acid for 3-chlorophenylboronic acid.
?? NMR (CDCl 3) d: 1.16-1.26 (4? M), 2.05 (3? S), 2.25-2.39 (1? M), 4.69-4. 88 (1H, m), 5.47-5.68 (1H, broad), 6.49 (1H, d), 6.84-6.97 (4H, m), 7.18-7.42 ( 7H, m). MS m / z 437 (M +), 439 (M + 2). (±) -Cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl] -N- (4-phenoxy-phenyl) - acetamide (B-51) (±) -cis-N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tet ahydro-quinolin-4-yl] -N was made - (4-phenoxy-phenyl) -acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and 4-chlorophenylboronic acid for 4-phenoxyphenylboronic acid. XH NMR (CDCl 3) d: 1.16-1.18 (4H, m), 2.06 (3H, s), 2.34-2.38 (1H, m), 4.74-4.82 ( 1H, m), 5.29 (1H, a), 6.47 (1H, d), 6, 83-7, 40 (16H, m). MS m / z: 496 (M + 1). (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -iV-pyridin-2-yl-acetamide ( B-52) (±) - cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -W-pyridin- was made 2-yl-acetamide following the general procedure B, substituting 4-dimethylaminobenzoyl chloride for it was carried out and the synthesis of N-pyridinyl instead of 4-chlorophenyl was carried out using the following procedure. Pd2 (dba) 3 (0.05 equiv.) And rac-BINAP (0.1 equiv.) Were added to a flask with degassed toluene and stirred for 1 h. To the previous solution, 2-bromopyridine (1.1 equiv.) And NaOtBu (1.1 equiv.) Were added and stirred for 30 min. (±) -cis- (4-amino-2-methyl-3, 4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone was dissolved in degassed toluene, added to the solution and heated at 100 ° C for 17. The reaction was diluted with ether, filtered through celite and concentrated. The compound was purified by Biotage with 20% EtOAc / 80% Hexane to 30% EtOAc / 70% Hexane to 50% EtOAc / 50% Hexane, yielding 43% of the product. Acetyl (±) - ci s- (3-methoxy-phenyl) - [2-met il -4 - (pyridin-2-ylamino) -3,4-dihydro-2H-quinolin-1-yl] -methanone was acetylated with acetyl chloride as described above, yielding (+) - cis-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4-yl] -N-pyridin-2-yl-acetamide. ¾ NMR (CDC13) d: 1.16 (d, 3H), 1.24 (t, 1H), 2.02 (s, 3H), 2.43 (m, 1H), 3.61 (s, 3H) ), 4.81 (sextuplet, 1H), 5.65 (sa, 1H), 6.52 (d, 1H), 6.75 (s, 1H), 6.79 (d, 2H), 6.90 (t, 1H), 7.07 (t, 1H), 7.14 (t, 1H), 7.25-7.33 (m, 2H), 7.49 (d, 1H), 7.77 ( t, 1H), 8.56 (s, 1H). MS m / z: 416.0 (M + 1). (+) -Cis-.V-cyclohexyl-.N- [1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-) 53) (±) - cis-W-cyclohexyl-N- [1- (3-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide was made following General procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride and synthesis of I-cyclohexyl in place of 4-chlorophenyl was performed using the following procedure. (±) - cis (4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone (1.0 equiv.) And cyclohexanone were dissolved. (1.0 equiv.) In ethanol and a catalytic amount of acetic acid was added. The reaction was stirred for -30 minutes, NaBH 4 (1.0 equiv.) Was added and stirred for a further 2 h at room temperature. More NaBH 4 (1.0 equiv.) Was added and stirred for a further 12 h. The reaction was concentrated and partitioned between CH2C12 and 1 N NaOH. The organic extracts were separated and dried over Na2SO4, filtered and concentrated. The compound was purified by Biotage with 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane, yielding 96% of the product. Cis- (+) - N- (4-cyclohexylamino-2-methyl-3, 4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone was acetylated with acetyl chloride as described above, giving ci s- (±) -JV-cyclohexyl-N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-ehydro-quinolin-4-yl] - acetamide. H NMR (CDC13) d: 1.1-1.45 (m, 6H), 1.5-1.75 (m, 3H), 1.85-2.1 (m, 3H), 2.3 ( s, 3H), 2.4 (m, 1H), 2.7 (m, 1H), 3.5 (c, 1H), 3.63 (s, 3H), 3.7 (m, 1H), 4.3 (dd, 1H), 4.90 (sextuplet, 1H), 6.6 (t, 1H), 6.7 (d, 1H) <; 6.8 (s, 1H), 6.85 (m, 2H), 7.0 (m, 3H). MS m / z: 421 (M + 1). (±) -Cis-N- (5-chloro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4 - il] -acetamide (B-54) (±) - cis-N- (5-chloro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl-1 was made , 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride and adding N-4-chloropyridinyl instead of 4 - chlorophenyl was performed using the following procedure To a flask were added Pd2 (dba) 3 (molar 0.05 equiv.) and rac-BINAP (0.1 equiv.) in degassed toluene and stirred for 1 h. To the above solution were added 2,5-dichloropyridinepyridine (1.1 equiv.) And NaC.sub.bu (1.1 equiv.) And stirred for 30 min. The corresponding amine, (+) - cis- (4-amino-2-methyl-3, 4-dihydro-2H-quinolin-1 -yl) - (3-methoxy-phenyl) -methanone was dissolved in degassed toluene, added to the solution and heated at 60 ° C for 40 h. The reaction was diluted with ether, filtered through celite and concentrated. The compound was purified by Biotage with 20% EtOAc / 80% Hexane, yielding 45% of the product. Acetyl (±) -cis- [4- (5-chloro-pyridin-2-ylamino) -2-methyl-3,4-dihydro-2H-quinolin-1-yl] - (3-methoxy-phenyl) was acetylated. -metanone with propionyl chloride as described above, giving (+) - cis-N- (5-chloro-pyridin-2-yl) -N- [1- (3-methoxy-benzoyl) -2-methyl- 1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide. XH RM (CDC13) d: 1.14 (t, 3H), 1.15 (d, 3H), 1.22 (m, 1H), 2.31 (m, 3H), 4.79 (sextuplete, 1H) ), 5.64 (sa, 1H), 6.44 (d, 1H), 6.81-6.92 (m, 3H), 7.10-7.22 (m, 4H), 7.43 ( d, 1H), 7.72 (dd, 1H), 8.50 (d, 1H). MS m / z: 452 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -iV- [1- (4-methoxy-benzoyl) -2,5-dimethyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -acetamide (B-55) (±) - Cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,5-dimethyl-1,2,3 was manufactured , 4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting aniline for 3-toluidine and -dimethylaminobenzoyl chloride for 4-methoxybenzoyl chloride. The reaction was not selective and (+) - cis- N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1,2,3 was also obtained. 4-tetrahydro-quinolin-4-yl] -acetamide in a 1: 1 mixture with the product. X H NMR (CDCl 3) d: 1.07 (d, 3 H), 1.25 (t, 1 H), 1.91 (s, 3 H), 2.15 (m, 1 H), 2.43 (s, 3 H) ), 3.76 (s, 3H), 4.26 (sextuplet, 1H), 6.28 (d, 1H), 6.33 (t, 1H), 6.58 (t, 1H), 6.62 (d, 2H), 6.77 (t, 1H), 6.88 (d, 3H), 7.28 (m, 2H), 7.44 (d, 1H). MS m / z: 463, 0 (M + 1) (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1, 2, 3, 4 - tetrahydro-quinolin-4-yl] -acetamide (B-56). (±) - Cis-N- (4-chloro-Ehenyl) -N- [1- (4-methoxy-benzoyl) ) -2,7-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, aniline by 3-toluidine and -dimethylaminobenzoyl chloride by 4 -rr chloride .ethoxybenzoyl The reaction was not selective and (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,5-dimethyl-l, 2,3 was also obtained. 4-tetrahydro-quinolin-4-yl] -acetamide in a 1: 1 mixture with the title compound. (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-l, 2,3,4-tetrahydro-quinolin-4 was removed -yl] -acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2R, 4S) - and (2S, 4i?) -cis-N- (4 - chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2,7-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-58 and B- 57, respectively). ¾ NMR (CDC13) d: 1.13 (d, 3H), 1.26 (t, 1H), 2.03 (s, 3H), 2.05 (s, 3H), 2.27 (m, 1H ), 3.76 (s, 3H), 4.75 (sextuplet, 1H), 5.59 (sa, 1H), 6.35 (s, 1H), 6.68 (d, 2H), 6.95 (d, 1H), 7.18 (m, 1H), 7.20 (d, 2H), 7.37 (d, 2H). MS m / z: 463.5 (M + 1) (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide (B-59) (+) - cis-N- (4-chloro-phenyl) -N- [1- (4 -fluoro benzoyl) -6-methoxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting aniline for 4-anisidine, 4-dimethylaminobenzoyl chloride 4-fluorobenzoyl chloride and propionyl chloride by acetyl chloride. ¾ NMR (300 Hz, CDCl 3) d: 1.08-1.22 (m, 7 H), 2.09-2.38 (m, 3H), 3.79 (s, 3H), 4.77 ( ddd, 1H), 5.58 (sa, 1H), 6.41-6.50 (m, 2H), 6.82-6.94 (m, 3H), 7.16-7.32 (m, 4H), 7.35-7.44 (m, 2H). S m / z = 481 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4 -yl] -propionamide (B-60) (±) - cis-N- (4-chlorophenyl) -N- [1- (4-fluoro-benzoyl-1) -6-hydroxy-2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide from (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6- methoxy-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -propionamide using the procedure described above for the preparation of (±) -cy-N- (4-chloro-phenyl) -N - [1- (4-Hydroxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. X H NMR (300 MHz, CDCl 3) d: 1.04-1.18 (m, 7 H), 2.07-2.41 (m, 5H), 4.76 (ddd, 1H), 5.50 ( sa, 1H), 6.27 (d, 1H), 6.36 (d, 1H), 6.65 (s, 1H), 6.70-6.91 (m, 3H), 7.03-7 , 44 (m, 4H).
MS m / z: 467 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2,7-dimethyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -propionamide (B-61) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl-1) -2,7-dimethyl-2,3, 4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting aniline for 3-toluidine, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride.
X H NMR (300 MHz, CDCl 3) d: 1.10 (m, 7 H), 2.04 (s, 3 H), 2.14-2.32 (m, 3 H), 4.74 (ddd, 1 H) , 5.57 (sa, 1H), 6.26 (s, 1H), 6.81-6.98 (m, 4H), 7.11-7.33 (m, 4H), 7.31-7 , 43 (m, 2H).
MS m / z: 465 (+ 1). Methyl ester of (+) - cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro -quinolin-6-yloxy] -acetic (B-62) Methyl ester of (±) - Cis- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro- benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy] -acetic from (±) -cis-N- (4-chloro-phenyl) -N- [1- ( 4-fluoro-benzoyl) -6-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the alkylation procedure of the phenol used to make (±) -ethyl ethyl ester cis-4 - (4 -. {4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenoxy) -butyric. Ethyl 4-bromobutyrate was replaced by methyl bromoacetate. ? NMR (300 MHz, CDC13) d: 1.07-1.22 (m, 7 H), 2.10-2.38 (m, 3H), 3.80 (s, 2H), 4.58 (s) , 3H), 4.75 (m, 1H), 5.54 (sa, 1H), 6.39 (m, 2H), 6.81-6.94 (m, 3H), 7.18-7, 35 (m, 5 H, 7.36-7.44 (m, 2H) MS m / z: 539 (M + 1). (±) -Cis-N- (4-Chloro-phenyl) -iV- [6- (2-diethylamino-ethoxy) -1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide (B-63) It was made (±) -cis-N- (4-chloro-phenyl) -N- [6- (2-diethylamino-ethoxy) -1- (4-fluoro-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro-quinolin-4-yl] -propionamide from (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2 - methyl -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide following the alkylation procedure of phenol used to make (+) - cis-4- (4- {4- [(4-Chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl] -.-phenoxy) -butyric acid was replaced by ethyl-4-bromobutyrate. -bromo-ethyl) -diethyl -amine ¾ NMR (300 MHz, CDCl 3) d: 0.95-1.11 (m, 13 H), 2.09-2.38 (m, 3H), 2.51-2.77 (m, 4H), 2.79-2.92 (ra, 2H), 3.86-4.08 (m, 2H), 4.76 (ddd, 1H), 5.58 (sa, 1H), 6.34-6, 51 (m, 2H), 6.78-6.94 (m, 3H), 7.14-7.31 (m, 4H), 7.37-7.42 (m, 2H). MS m / z: 566 (M + 1). Ethyl (±) -cis- 2 - [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4 ethyl ester -tetrahydro-quinolin-6-yloxy] -2-methyl-propionic acid (B-64) (+) - cis- 2 - [4 - [(4-chloro-phenyl) -propionyl-amino] ethyl ester was manufactured] -1- (4-fluoro-benzoyl) -2-methyl-, 1,2,3,4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic was manufactured from (±) - cis-N- (4-chloro-enyl) -N- [1- (4-fluoro-benzoyl) -6-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the procedure of alkylation of phenol used to make (+) - cis-4- (4 -. {4 - [(4-chlorophenyl) -propionyl-amino] -2-methyl-3,4-dihydro) ethyl ester -2H-quinoline- 1 -carbonyl.} - phenoxy) -butyric acid. Ethyl 4-bromobutyrate was replaced by 2-bromo-2-methyl-propionic acid ethyl ester. X H NMR (300 MHz, CDCl 3) d: 1.13-1.28 (m, 10 H), 1.56 (s, 3H), 1.58 (s, 3H), 2.16-2.29 (m, 3H), 4.73 (ddd, H), 5.56 (ss, 1H), 6.31-6.39 (m, 2H), 6.76-6.88 (m, 3H), 7.16-7.22 (m, 4H), 7.38-7.41 (m, 2H). MS m / z: 581 (M + 1).
Acid (±) -cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinoline- 6-yloxy] -acetic acid (B-65) Acid (±) -cis- [4 - [(4-chloro-phenyl) -propionyl-araino] -1- (4-f luoro-benzoyl) -2- methyl -1, 2,3, -tetrahydro-quinolin-6-yloxy] -acetic acid from (±) -cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4) methyl ester -fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-6-yloxy] -acetic acid. To a solution of (±) -cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3-methyl ester. , 4-tetrahydro-quinolin-6-yloxy] -acetic acid (83 mg, 0.155 mmol) in methanol (3 mL) was added sodium hydroxide (1 M in water, 310 μl, 0.310 mmol). The reaction was stirred at room temperature 3 h and concentrated under reduced pressure to remove the methanol. The pH of the remaining aqueous solution was adjusted to 6 with 1 M hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the carboxylic acid (76 mg, 94%). XH RM (300 MHz, CDC13) d: 1.09-1.26 (m, 7 H), 2.08-2.18 (m, 3H), 4.58 (AB q, 2H), 4.79 (ddd, 1H), 5.57 (sa, 1H), 6.40 (m, 2H), 6.86 (m, 3H), 7.09-7.30 (m, 4H), 7.35- 7.46 (m, 2H), 8, 18 (br s, 1H). MS m / z: 523 (-1). Acid (±) -cis-2- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro- quinolin-6-yloxy] -2-methyl-propionic acid (B-66) Acid (±) -cis-2- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4- fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic acid from (±) - ci s-2 - [4 -] [(4-Chloro-phenyl) -propionyl-amino] -1 - (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yloxy] -2-methyl-propionic . The saponification conditions detailed in the procedure for the synthesis of (+) - cis- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2- acid were used. methyl-l, 2,3,4-tetrahydro-quinol ind 6-yloxy] -acetic acid. XH NMR (300 Hz, CDC13) d: 1.04-1.21 (m, 7 H), 1.54-1.66 (m, 6H), 2.12-2.37 (m, 3H), 4.77 (ddd, 1H), 5.53 (sa, 1H), 6.37 (d, 1H), 6.48 (d, 1H), 6.66-6.92 (m, 1H), 7 , 12-7.26 (m, 4H), 7.43 (m, 2H), 9.00 (ss, 1H). MS m / z: 553 (M + 1). (+) -Cis-N- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro) phenyl) -propionamide (B-67) (±) -cis-N- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline was prepared -4-yl] -N- (4-chloro-phenyl) -propionamide from (±) - ci s-4 - [(4-chloro-phenyl) -propionyl-amino] - 1 - (-) - methyl ester ( 4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-6-yloxy] -acetic acid. A (±) -cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-f-luoro-benzoyl) -2-methyl-l, 2,3,4-methyl ester solid tetrahydro-quinoline-6-yloxy] -acetic acid (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2.10 ml). The resulting solution was stirred overnight at room temperature and concentrated. The resulting crude amide was purified by chromatography on silica gel (gradient of 100% hexanes-100% ethyl acetate) yielding the pure product (59 mg, 76%).
X H NMR (300 MHz, CDCl 3) d: 1.10-1.23 (m, 7 H), 2.16-2.39 (m, 3H), 4.44 (s, 2H), 4/77 ( ddd, 1H), 5.56 (sa, 1H), 6.25 (sa, 1H), 6.40-6.62 (m, 3H), 7.16-7.26 (m, 4H), 7 , 35-7.48 (m, 2H). MS m / z: 524 (M + 1). (+) -Cis-N- [6-Bromo-1- (4-fl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -iV- (4 - chloro-phenyl) -propionamide (B-69) (±) - cis- N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-, 2,3-, -hydroxy- quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide following general procedure B, substituting 4-bromoaniline for aniline and 4-dimethylaminobenzoyl chloride for 4-f luorobenzoyl chloride and propionyl chloride for acetyl chloride. ¾ NMR (CDCl 3) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 4.8 (1H, m), 5.6 (1H, m), 6.4 (1H, d), 6.9 (3H, t), 7.1 (1H, m), 7.2 (4H, m) , 7.4! 3 H, m). MS m / z: 531 (M + 2). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-6-morpholin-4-yl- 1, 2, 3, 4-tetrahydro -quinolin-4-yl] -propionamide (B-70) (±) - cis- N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-6 was made -morpholin-4-yl-1,2,3, 4-te rahydro-quinol-4-yl] -propionamide from (±) - cis- N- [6-bromo-1- (4-fluoro- benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -N- (4-chloro-phenyl) -propionamide. It was dissolved (+) - cis- N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol in 4 -yl] - N- ( 4-chloro-phenyl) -propionamide in toluene, followed by Pd2 (dba) 3, BINAP, sodium tert-butoxide and morpholine. The reaction mixture was heated at 90 ° C for 24 hours. The reaction mixture was cooled to room temperature, filtered through Celite ® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethylacetate (10-50%). XH RM (CDC13) d: 1.1-1.2 (7H, m), 2.1-2.3 (3H, m), 3.1 (4H, t), 3.8 (4H, t), 4.8 (1H, m), 5.6 (1H, m), 6.3 (1H, d), 6.4 (1H, m) , 6.7 (1H, s), 6.9 (3H, m), 7.1-7.4 (5H, m). S m / z: 536 (M + l). (+) -Cis- (4-chloro-phenyl) -N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4- il] -propionamide (B-71) (+) - cis-N- (4-chloro-phenyl) -N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide in the same manner as (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) - 2-methyl-6-morpholin-4-yl-1,2,3-tetrahydro-quinolin-4-yl] -propionamide with the exception that morpholine was replaced by diethylamine. The reaction was not selective and yielded (+) - cis-N- [6-diethylamino-1- (4-fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-diethylamino-phenyl) -propionamide in addition to the title compound. X H NMR (CDCl 3) d: 1.1-1.3 (13 H, m), 1.6 (1 H, m), 2.1-2.3 (3 H, m), 3.3 (4 H, m ), 4.7 (1H, m), 5.6 (1H, m), 6.2 (1H, m), 6.3 (1H, m), 6.5 (1H, s), 6.9 (2H, m), 7.3 (4H, m), 7.4 (2H, m). MS m / z: 523 (M + 2). (±) -Cis-N- [6-diethylamino-l- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-diethylamino) phenyl) -propionamide (B-72) (±) - ci sN- [6 -diethi lamino- 1 - (- fluoro-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinoline- 4 -yl] -N- (4-diethylamino-phenyl) -propionamide in the same manner as (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) - 2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-quinol-4-yl] -propionamide with the exception that morpholine was replaced with diethylamine. The reaction was not selective and yielded (+) - cis-N- (4-chloro-phenyl) -N- [6-diethylamino- 1 - (-fluoro-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide in addition to the title compound. 1 H NMR (CDC13) d: 1.1-1.3 (19 H, m), 2.3 (3 H, m), 3.3 (8 H, m), 4.7 (1 H, m), 5, 6 (1H, m), 6.1 (1H, m), 6.2 (1H, m), 6.6 (3H, m), 6.9 (1H, m), 7.1 (3H, m ), 7.3 (2H, m). MS m / z: 560 (M + 2). Acid (±) -cis-3- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-6-yl] -acrylic (B-73) (±) - cis- 3 - [4 - [(4-Chloro-phenyl) -propionyl-amino] - 1- (4-Fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-6-yl] -acrylic acid from (±) - cis-N- [6-bromo- 1- (4-Fluoro-benzoyl) -2-methyl-1,2,3-tetrahydro-quinol-4-yl] -N- (4-chloro-phenyl) -propionamide. To a solution of (±) - cis-N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide (250 mg, 0.47 mmol), TEA (0.2 mL, 1.4 mmol), palladium acetate (11 mg, 0.047 mmol) and 1,3-bis (diphenylphosphino) propane (39 mg, 0.094 mmol) in 10 ml DMF was added 0.13 ml methyl acrylate (1.41 mmol). The resulting reaction mixture was heated at 80 ° C overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (2: 3), to give (±) -cis-3- [4- [(4-chloro-phenyl) -propionyl) methyl ester. -amino] -1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl] -acrylic acid (110 mg, 44%). To a solution of (+) - cis-3- [4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2-methyl ester. , 3,4-tetrahydro-quinolin-6-yl] -acrylic acid (110 mg, 0.21 mmol) in 4 mL of methanol was added 50 mg of K2CO3, (0.36 mmol, in 2 mL of water). The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed in vacuo. 1 M HC1 was added until the mixture was acidic. Dichloromethane (25 ml) was added. The organic phase was dried with magnesium sulfate. The dichloromethane was removed in vacuo. The residue was purified by HPLC to give 10 mg of the title compound. XE NMR (CDC13) d: 1.0-1.2 (7H, m), 2.4 (2H, m), 2.5 (1H, m), 3.3 (1H, a), 4.8 (1H, m), 5.6 (1H, m), 6.4 (1H, d), 6.6 (1H, d), 7.0 (2H, t), 7.2-7.6 ( 9H, m). MS m / z: 522 (M + 2). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2,8-dimethyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -acetamide (B-74) (±) -Cis-N- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2,8-dimethyl-2,3 was manufactured , 4-etrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 2-toluidine and was carried out for 4-dimethylaminobenzoyl chloride. X H NMR (CDCl 3) d: 1.11 (3 H, d; overlap 1H, t), 1.76 (3H, s), 2.00 (3H, s), 2.35 (1H, m), 3.55 (3H, s), 5.00 (1H, m) , 5.60 (1H, m), 6.65 (1H, s), 6.80 (1H, t), 6.85 (lH, t), 6.95 (1H, t), 7.15 ( 1H, t), 7.25 (1H, tj, 7.25-7.55 (6H, m) MS m / z: 429 (M + 1). (±) -Cis-N- (4-Chloro- phenyl) -N- [1- (3-methoxy-benzoyl) -2,6-dimethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (B-75) It was manufactured (±) - Cis-N- (-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2,6-dimethyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following General procedure B, substituting aniline for 4-toluidine and performed for 4-dimethylaminobenzoyl chloride, LH RN (CDC13) d: 1.12 (3H, d, overlap 1H, t), 2.02 (3H, s) ), 2.33-2.35 (3H, s overlap 1H, m), 3.63 (3H, m), 4.80 (1H, m), 5.60 (1H, m), 6.44 ( 1H, d), 6.70-6.85 (3H, complex), 7.05 (1H, t), 7.15 (1H, s), 7.25-7.55 (6H, complex). m / z: 429 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (3-methoxy-benzoyl) -2-methyl-6-trifluorom ethyl-l, 2, 3, 4-etrahydro-quinolin-4-yl] -acetamide (B-76) (±) - Cis-N- (4-chloro-phenyl) -N- [1 - (3 -methoxy-benzoyl) -2-methyl-6-trifluoromethyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 4-trifluoromethylaniline and carried out for 4-dimethylaminobenzoyl. X H NMR (CDCl 3) d: 1.15 (3 H, d; overlap 1 H, t), 2.03 (3H, s), 2.38 (1H, m), 3.63 (3H, s), 4.80 (1H, m), 5.60 (1H, m), 6.60 (1H, d) , 6.70 (1H, d), 6.80 (1H, dd), 7.15 (1H, t), 7.25-7.40 (6H, m), 7.60 (1H, s). MS m / z: 483 (M + 1).
(+) -Cis-N- (-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4- il] -acetamide (B-77) (±) - cis-N- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 4-methoxyaniline and was carried out for 4-dimethylaminobenzoyl chloride. XH RM (CDC13) d: 1.12 (3H, d; overlap 1H, t), 2.02 (3H, s), 2.35 (1H, m), 3.63 (3H, s), 3, 76 (3H, s), 4.80 (1H, m), 5.60 (1H, m), 6.44 (1H, s), 6.70-6.95 (4H, complex), 7.15 (1H, t), 7.25-7.55 (6H, m). MS m / z: 445 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (B-78) (±) -cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (thiophene-2-carbonyl) -6-trifluoromethyl-1 was made , 2,3, 4 - tetrahydro-quinoline-4-yl] -acetamide following the general procedure B, substituting aniline for 4 -trifluorometilanilina and 4-dimethylaminobenzoyl chloride for 2-thiophenecarbonyl chloride of.
X H NMR (CDCl 3) d: 1.14 (3 H, d; overlap 1 H, t), 2.02 (3 H, s), 2.35 (1 H, m), 4.80 (1 H, m), 5, 65 (1H, m), 6.65 (1H, d), 6.80 (1H, d), 7.00 (1H, d), 7.20 (overlap 2 x 1H, d), 7.24- 7.42 (3H, m), 7.60 (1H, s). MS m / z: 539 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -IV- [2-methyl-1- (5-methyl-thiophene-2-carbonyl) -6- trifluoromethyl- 1, 2, 3, 4-tetrahydro -quinolin-4-yl] -acetamide (B-79) (±) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1 - (5-methyl-thiophene-2 - carbonyl) - 6-trifluoromethyl-1, 2,3,4- tetrahydroquinoline-4 -yl] -acetamide following the general procedure B, substituting aniline for 4-trifluoromethylaniline and 4-dimethylaminobenzoyl chloride for 5-methyl chloride - 2 -thiophenecarbonyl. 1 H NMR (CDC13) d: 1.14 (3H, d; overlap 1H, t), 2.02 (3H, s), 2.35 (1H, m), 2.40 (3H, s), 4.80 (1H, m), 5.65 (1H, m), 6.45 (1H, d) , 6.55 (1H, d), 7.00 (1H, d), 7.20 (overlap 2 x 1H, d), 7.24-7.42 (3H, m), 7.55 (1H, s). MS m / z: 554 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-7-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 - il] -propionamide (B-80) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-7-trifluoromethyl-1 was made , 2,3, 4 - tetrahydroquinoline-4-yl] -propionamide following the general procedure B, substituting aniline for 3 - trifluoromet ylaniline chloride, 4-dimethylaminobenzoyl by 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride . The isomer mixture was obtained from positions 5 and 7. XH NMR (CDCl3) d: 1.15 (3H, d; overlap 1H, t), 2.20-2.40 (2H, c; 1H, m), 4.80 (1H, m), 5.65 (1H, m), 6.70 (1H, s), 6.95 (2 x 1H, t), 7.10-7.60 (8H, m) MS m / z: 519 (M + 1). (±) -Cis-N- [7-bromo-l- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro) phenyl) -acetamide (B-81) (±) -cis-N- [7-bromo-l- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin was made -4-yl] -N- (-chloro-phenyl) -acetamide following the general procedure B, substituting aniline for 3-bromoaniline. A mixture of the isomer of positions 5 and 7 was obtained. (±) -Cis-N- (4-chlorophenyl) -N- [1- (4-dimethylamino-benzoyl) -7-isopropyl-2-methyl- 1, 2, 3, 4- tetrahydro-q inolin-4-yl] -acetamide (B-82) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4 - dimethylamino-benzoyl) -7-isopropyl-2-methyl-1,4,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting aniline for 3-isopropylaniline. A mixture of the isomer was obtained from positions 5 and 7. XH NMR (CDC13) d: 0.89 (2 x 3H, t), 1.15 (3H, d; overlap 1H, t), 2.01 (3H , s), 2.33 (1H, m), 2.60 (1H, m), 2.87 (2 x 3H, s), 4.80 (1H, m), 5.65 (1H, m), 6.40 (overlap 1H, s, 2H, d), 6.90 (1H, d), 7.10 (1H, d), 7.15-7.35 (5H, m) 7.40 (1H, d). S m / z: 505 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-7-morpholin-4-yl-l, 2,3, 4-tetrahydro -quinolin-4-yl] -acetamide (B-83) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-7 was made -morpholin-4-yl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide from (±) - cis-N- [7-bromo-1- (4-dimethylamino-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl] -JV- (4-chloro-phenyl) -acetamide. (±) -cis-N- [7-bromo-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -N- (4 -chloro-phenyl) -acetamide in toluene, followed by Pd2 (dba) 3, BINAP, sodium c-butoxide and morpholine. The reaction mixture was heated at 90 ° C for 24 hours. The reaction mixture was cooled to room temperature, filtered through Celite ® and concentrated. The crude mixture was purified by flash chromatography on silica gel using an elution gradient of hexane-ethylacetate (10-50%). XH NMR (CDCl 3). d: 1.11 (3H, d; overlap 1H, t), 1.99 (3H, s), 2.33 (1H, m), 2.60-2.80 (2 x 2H, m), 2.89 (2 x 3H, s), 3.70 (2 x 2H, m), 4.70 (1H, m), 5.60 (1H, m), 6.10 (1H, s), 6.44 (2 x 1H, d), 7 , 00-7.40 (8H, m). MS m / z: 548 (M + 1). (+) -Cis-N- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-diethylamino) phenyl) -acetamide (B-84) (±) -cis-N- [7-diethylamino-l- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin was manufactured - 4-yl] -N- (4-diethylamino-phenyl) -acetamide in the same manner as (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-7-morpholin-4-yl-l, 2,3,4-tetrahydro-quinol in-4-y1] -acetamide with the exception that morpholine was replaced by diethylamine. The reaction was not selective and yielded (±) - cis-N- (4-chloro-phenyl) -N- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-yl] -acetamide in addition to the title compound. X H NMR (CDCl 3) d: 0.78 (2 x 3 H, t), 1.15 (overlap 3 H, d; 1 H, t), 1.98 (3 H, s), 2.33 (1 H, m), 2.87 (2 x 3H, s), 2.90-3.10 (2 x 2H, c), 4.70 (1H, m), 5.60 (1H, m), 5.90 (1H, s), 6.46 (3 x 1H, d), 7, 00-7, 40 (7H, m). MS m / z: 557 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [7-diethylamino-1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-qriinolin-4 - il] -acetamide (B-85) (±) - ci sN- (4-chloro-phenyl) -N- [7-dimethylamino- 1- (4-dimetheylamino-enzoi 1) -2-methyl was manufactured -l, 2,3,4-tetrahydro-quinol-4-yl] -acetamide in the same manner as (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino -benzoyl) -2-methyl-7-morpholin-4-yl -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide with the exception that morpholine was replaced by diethylamine. The reaction was nonselective and yielded (±) -cis-N- [7-diethylamino-l- (4-dimet i lamino-benzoi 1) -2 -me il -1,2,3,4 -te rahydro-quinolin -4 -yl] -N- (4-diethylamino-phenyl) -acetamide in addition to the title compound. ¾ NMR (CDC13) d: 0.78 (2 x 3H, t), 1.15 (overlap 2 x 3H, t; 3H, d; 1H, t), 2.00 (3H, s), 2.33 (1H, m), 2.76 (2 x 3H, s), 2.80-3.00 (2 x 2H, c), 3.24 (2 x 2H, c), 4.60 (1H, m ), 5.60 (1H, m), 5.90 (1H, s), 6.46 (2 x 1H, d), 6.60 (1H, m), 6.90 (2 x IB ", d ), 7.00-7.20 (6H, m) MS m / z: 609 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4 -fluoro-benzoyl) -5-methoxy-2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide (B-86) (±) - cis-N- (4 - chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -5-methoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the general procedure B, substituting aniline for 3-anisidine, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride. lH NMR (CDCl3) d: 1.09-1.14 (6H, m), 1, 50-1.66 (1H, m), 1.97-2.34 (3H, m), 3.83 (3H, s), 4.65 (1H, c), 5.70-5.80 (1H, a), 6.08 (1H, d), 6.68 (1H, d). 6.81-6.89 (3H, m), 7.14-7.18 (4H, m), 7.33-7.36 (2H, m). MS m / z: 481 (M + 1). 4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-7-yl-acid ester ( ±) -cis-2, 2-dimethyl-propionic (B-87) 4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1 was prepared , 2,3, 4-tetrahydro-quinolin-7-ylster of (+) - cis-2,2-dimethyl-propionic acid following general procedure B, substituting aniline for 3-amino-phenyl-2-acid ester , 2-dimethyl-propionic. XH NMR (CDC13) d: 1.11-1.25 (13H, m), 2.02 (3H, s), 2.20-2.40 (1H, m), 2.92 (6H, s) , 4.60-4.72 (1H, m), 5.45-5.55 (1H, a), 6.26 (1H, s), 6.46 (2H, d), 6.85 (1H , d), 7.09-7.39 (7H, m). MS m / z: 562 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (B-88) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-dimet-lamino-benzol1) -7-hydroxy-2 -met was made il-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide from 4- [acetyl- (4-chloro-phenyl) -amino] -1 - (4-dimethylamino-benzoyl) -2 -I-1, 2,3,4-tetrahydro-quinolin-7-yl ester of (±) -cis-2,2-dimethyl-propionic acid. 4- [Acetyl- (4-chloro-phenyl) -amino] -1- (-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-7-yl ester of the acid was dissolved (± ) -cis-2, 2-dimethyl-propionic acid (100 mg, 0.178 mmol) in tetrahydrofuran and sodium hydroxide (1 M, 356 μ ?, 0.356 mmol) was added thereto. The mixture was stirred at room temperature for 4 hours and then heated to reflux for 2 h. The mixture was cooled to rt, acidified, concentrated and purified by chromatography on silica gel (20 mg, 23%).
XH NMR (MeOD) d: 1.06-1.08 (4H, m), 2.00 (3H, s), 2.35-2.45 (1H, m), 2.93 (6H, s) , 4.65-4.68 (1H, m), 5.42-5.50 (1H, a), 6.07 (1H, s), 6.53 (2H, d), 6.63 (1H , d), 7.10-7.20 (3H, m), 7, 35-7, 48 (4H, m). MS m / z: 478 (M + 1). Ethyl ester of (+) - cis- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro -quinolin-7-yloxy] -acetic acid (B-89) (±) - cis- [4 - [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-) ethyl ester was prepared. benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-7-yloxy] -acetic from (±) -cis-N- (4-chloro-phenyl) -N- [1- ( 4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide, following the alkylation conditions described for the synthesis of ethyl ester of the acid (+ ) -cis-4- (4- { 4- [(4-Chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} -phenoxy ) -butyric, substituting ethyl 4-bromobutyrate for ethyl bromoacetate. XH NMR (MeOD) d: 1.10-1.38 (7H, m), 2.00 (3H, s), 2.39-2.45 (1H, m), 2.94 (6H, s) , 4.04-4.20 (2H, m), 4.29 (2H, s), 4.60-4.75 (1H, m), 5.40-5.50 (1H, a), 6 , 16 (1H, s), 6.54 (2H, d), 6.79 (1H, d), 7.08 (2H, d), 7.20-7.48 (5H, m). MS m / z: 564 (M + 1). (±) -Cis-2 - [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,3,4-tetrahydro-quinoline -7-allyl] -acetamide (B-90). (±) -cis-2- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2 was prepared. -methyl-l, 2, 3, 4-tetrahydro-quinolin-7-yloxy] -acetamide from (±) -cis- [4- [acetyl- (4-chloro-phenyl) -amino] ethyl ester] -1- (4-dimethylamino-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin-7-yloxy] -acetic, by the same amidation procedure used in the synthesis of (+) - cis -N- [6-carbamoylmethoxy-1- (4-fluoro-benzoyl) -2-methyl-1,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -propionamide . XH NMR (MeOD) d: 1.09-1.15 (4H, m), 2.00 (3H, s), 2.39-2.45 (1H, m), 2.94 (6H, s) , 4.04-4.20 (2H, m), 4, 60-4, 75 (1H, m), 5.40-5.50 (1H, a), 6.14 (1H, s), 6 , 53 (2H, d), 6.81 (1H, d), 7.09 (2H, d), 7.20-7.48 (5H, m). MS m / z: 535 (M + 1). Acid (±) -cis- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,3,4-tetrahydro-quinoline- 7-yloxy] -acetic acid (B-91) (+) - cis- [4- [Acetyl- (4-chloro-phenyl) -amino] -1- (-dimethylamino-benzoyl) -2-methyl- acid was prepared 1, 2, 3, 4 - tetrahydro-quinolin-7-yloxy] -acetic acid from (+) - cis- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy] -acetic following the saponification procedure described above for the synthesis of (+) - cis- [4] acid - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol-6-yloxy] -acetic. XH NMR (MeOD) d: 1.08-1.10 (4H, m), 1.98 (3H, s), 2.39-2.45 (1H, m), 2.93 (6H, s) , 4.20 (2H, s), 4.61-4.70 (1H, m), 5.40-5.50 (1H, a), 6.17 (1H, s), 6.53 (2H , d), 6.79 (1H, d), 7.08 (2H, d), 7.28-7.48 (5H, m). MS m / z: 536 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7- (2-hydroxy-2-methyl-propoxy) -2-methyl-1, 2 , 3, -tetrahydro-quinolin-4-yl] -acetamide (B-92) was prepared (±) - ci sN- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7 - (2-hydroxy-2-methyl-propoxy) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide from ethyl ester of (±) - cy s- [ 4 - [Acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethyl-1-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy] -acetic ester using the same alkylation procedure described for the synthesis of (±) - cis-N-. { 1 - [4 - (2-Hydroxy-2-methyl-propoxy) -benzoyl] -2-metyl-1,2,3,4-tetrahydro-quinolin-4-yl} -N- phenyl-pro-ionamide. XH NMR (CDC13) d: 1.01-1.20 (4H, m), 1.30 (6H, s), 2.01 (3H, s), 2.20-2.40 (1H, m), 2.92 (6H, s), 3.70 (2H, s), 4.65-4.72 (1H, m), 5.45-5.55 (1H, a), 6.13 (1H, s), 6.45 (2H, d), 6.65 (1H, d), 7.12-7.46 (7H, m). MS m / z: 551 (M + 1). (+) -Cis - -N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-ethoxy-2-methyl-1,2,3,4-tetrahydro-quinoline- 4-yl] -acetamide (B-93) (±) - ci sN- (4-Chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-ethoxy-2-methyl-1 was manufactured , 2,3, 4- tetrahydro-quinolin-4-yl] -acetamide from (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7 -hydroxy-2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide using the same alkylation procedure described for the synthesis of (±) - cis-4 - (4) ethyl ester - { 4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl.} - phenoxy) -butyric, substituting 4-bromobutyrate of ethyl by ethyl iodide. X H NMR (CDCl 3) d: 1.01-1.20 (7H, m), 2.01 (3H, s), 2.20-2.40 (1H, ra), 2.92 (6H, s) , 3.60 (2H, c), 4.65-4.72 (1H, m), 5.45-5.55 (1H, a), 6.15 (1H, s), 6.44 (2H , d), 6.69 (1H, d), 7, 11-7.46 (7H, m). MS m / z: 506 (M + 1). Ethyl ester of (±) -cis-4- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-l, 2, 3, 4 - tetrahydro-quinolin-7-yloxy] -butyric acid (B-94) (±) -cis-4- [4 - [acetyl- (4-chloro-phenyl) -amino] -1- ( 4-dimethylamino-benzoyl) -2-methyl-1,2,3,4-ehydro-quinolin-7-yloxy] -butyric from (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -7-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -acetamide using the same alkylation procedure described for ester synthesis Ethyl (+) - cis-4 - (4 - { 4 - [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3, 4-dihydro-2H-quinoline-1- carbonyl.}. -phenoxy) -butyric. LH NMR (CDCl 3) d: 1.09-1.11 (4H, m), 1.23 (3H, t), 1.81-1.85 (2H, m), 2.01 (3H, s) , 2.30-2.33 (3H, m), 2.92 (6H, s), 3.50-3.54 (1H, m), 3.72-3.76 (1H, m), 4 , 09 (2H, c), 4.66-4.73 (1H, m), 5.57-5.63 (1H, m), 6.14 (1H, s), 6.46 (2H, d) ), 6.68 (1H, d), 7.11-7.39 (7H, m). MS m / z: 593 (M + 1). Acid (±) -cis-4- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) -2-methyl-1,3, 4- tetrahydro- quinolin-7-yloxy] -butyric acid (B-95) Acid (±) -cis-4- [4- [acetyl- (4-chloro-phenyl) -amino] -1- (4-dimethylamino-benzoyl) was made -2-methyl-l, 2,3,4-tetrahydro-quinolin-7-yloxy] -butyric acid from (±) -cis-4- [4- [acetyl- (4-chloro-phenyl)] ethyl ester ) -amino] -1- (4-dimethylamino-benzoy1) -2-methyl-1,2,4,4-tetrahydro-quinolin-7-yloxy] -butyric following the saponification conditions described for the synthesis of acid ( ±) - cis- [4 - [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline- 6 - iloxy] -acetic. XH RM (CDC13) d: 1.08-1.11 (4H, m), 1.80-1.86 (2H, m), 1.99 (3H, s), 2.28-2.35 ( 3H, m), 2.89 (6H, s) 3.37-3.46 (1H, m), 3.66-3.73 (1H, m), 4.64-4.72 (1H, m ), 5.54-5.63 (1H, m), 6.07 (1H, s), 6.52 (2H, d), 6.67 (1H, d), 7.08-7.36 ( 7H, m).
MS m / z: 564 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2,7-dimethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl ] -acetamide (B-96). (+) - cis-N- (4-chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2,7-dimethyl-1,2,3 was manufactured , 4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure B, substituting aniline for 3-toluidine. In this procedure, the isomers of positions 5 and 7 were obtained. ¾ NMR (CDCI3) d: 1.11 (3H, d), 1.45-1.59 (4H, m), 2.02-2.07 (3H, m), 2.24-2.28 (1H, m), 2.92 (6H, s) 4, 67-4, 74 (1H, m), 5.52-5.59 (1H, m), 6.43-6.45 (3H, m), 6.95 (1H, d), 7.13-7.22 (6H, m), 7.35-7.43 (1H, m) . MS m / z: 307 (M). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenethyl-1,2,3-tetrahydro-quinolin-4-yl] - propionamide (B-97) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenethyl-1,2,3,4-tetrahydro was manufactured -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for 3-phenylpropionaldehyde and propionyl chloride for acetyl chloride.
?? NMR (CDCl 3) d: 1.16 (dt, 3H), 1.25 (m, 1H), 1.54 (m, 1H), 1.97 (m, 1H), 2.30 (m, 3H) , 2.56 (t, 2H), 4.85 (sextuplet, 1H), 5.66 (sa, 1H), 6.44 (d, 1H), 6.86 (t, 2H), 6.93 ( m, 2H), 7.03 (d, 2H), 7.12-7.29 (m, 8H), 7.37 (d, 2H). MS m / z: 542 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -iV- [2- (2-cyano-ethyl) -1- (4-fluoro-benzoyl) - 1, 2, 3, 4-tetrahydro-quinolin -4 -yl] -propionamide (B-98). (+) - cis-N- (4-chloro-phenyl) -N- [2- (2-cyano-ethyl) -1- (4-fluoro- benzoyl) -1,2,4,4-ehydro-quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for 4-oxobutyrylnitrile and propionyl chloride for acetyl chloride. ¾ NMR (300 MHz, CDC13) d: 1.19-1.23 (m, 4H), 1.65-1.79 (m, 2H), 2.07-2.57 (m, 5H), 4.90 (ddd, 1H), 5.61 (sa, 1H), 6.61 (d, 1H), 6.86 ( m, 2H), 6.95 (dd, 1H), 7.14-7.43 (m, 8 H). MS m / z = 490 (M + 1). (±) -Cis-N- [2-ethyl-l- (3-methoxy-benzoyl) -1, 2, 3, 4-tetrahydro-quinolin-4-yl] -IV- phenyl-acetamide (B-99) (±) -cis-N- [2-ethyl-1- (3-methoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was prepared following the procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride, acetaldehyde for propionylaldehyde and 4-chlorophenylboronic acid for phenylboronic acid. 2 H NMR (CDCl 3) d: 0.8 (3 H, t), 1, 3 (2 H, m), 1.6 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m ), 3.7 (3H, s), 4.7 (1H, m), 5.7 (1H, m), 6.5 (1H, d), 6.7 (1H, s), 6.8 (2H, rr.), 6.9-7.4 (9H, m) MS m / z: 429 (M + l). (±) -Cis-N- [1- (3-methoxy-benzoyl) -2-phenyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (B-100) (±) -cis-N- [1- (3-methoxy-benzoyl) -2-phenyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide was made following the procedure B, substituting 4-dimethylaminobenzoyl chloride for 3-methoxybenzoyl chloride, acetaldehyde for benzaldehyde and 4-chlorophenylboronic acid for phenylboronic acid. ? NMR (CDC13) d: 1.5 (1H, m), 2.0 (3H, s), 2.5 (1H, m), 3.6 (3H, s), 5.7 (1H, t) 5.8 (1H, m), 6.6 (1H, d), 6.9 (2H, m), 6, 9-7, 4 (15H, m). MS m / z: 494 (M-18). Ethyl (±) -cytos-4 - (acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,3, 4-tetrahydro-quinoline-2-carboxylic acid ester (B-101) (±) -cis-4- (Acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid ethyl ester was manufactured following the procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for ethyl glyoxylate and 4-chlorophenylboronic acid for phenylboronic acid. X H NMR (CDCl 3) d: 1.2 (3 H, t), 1.2 (1 H, m), 2.0 (3 H, s), 2.5 (1 H, m), 4.1 (2 H, c ), 5.0 (1H, t), 5.7 (1H, m), 6.6 (1H, d), 6.8-7.0 (4H, d), 7.1-7.4 ( 8H, m). MS m / z: 461 (M + 1). Acid (±) -cis-4- (acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,3, 4-tetrahydro-quinoline-2-carboxylic acid (B-102) Acid was made (+) - cis-4- (acetyl-phenyl-amino) -1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinoline-2-carboxylic acid from ethyl ester (± ) -cis-4- (acetyl-phenyl-amino) -1 - (3-methoxy-benzoyl) -1,2,3,4-tetrahydro-quinoline-2-carboxylic acid by basic hydrolysis with 1 N sodium hydroxide, ethanol and Water. XH NMR (CDC13) d: 1.2 (1H, m), 2.0 (3H, s), 2.6 (1H, m), 5.0 (1H, t), 5.6 (1H, m), 6.6 (1H, d), 6.9-7.0 (3H, m), 7.2 (2H, m), 7 , 3-7.5 (7H, m). MS m / z: 433 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-propyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] - propionamide (B-103) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-propyl-l, 2, 3, 4-tetrahydro was made -quinolin-4-yl] -propionamide following general procedure B, substituting 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride, acetaldehyde for butyraldehyde and propionyl chloride for acetyl chloride. XH NMR (CDCI3) d: 0, 8 (3H, t), 1.1-1.2 (7H, m), 1.4 (1H, m), 2.1-2.3 (3H, m), 4.8 (1H, ), 5.6 (1H, m), 6.7 (1H, d), 6.9-7.1 (4H, m), 7.2-7.5 (7H, m). MS m / z: 479 (M + 1). 4- [(4-Chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinolin-2-ylmethyl-ester (±) -cis acid -propionic (B-104) 4 - [(4-Chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -1,2,4,4-tetrahydro-quinolin-2-ylmethyl was prepared - (+) - cis-propionic acid ester following general procedure B, substituting acetaldehyde for 2-oxo-ethyl ester of propionic acid, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride .
? MRI (CDCl 3) d: 0.8 (3H, t), 1.1 (3H, t), 1.1 (1H, m), 2.1 (2H, m), 2.2 (3H, s) , 3.8 (1H, m), 4.2 (1H, m), 5.0 (1H, m), 5.4 (1H, m), 6.4 (1H, d), 6.8 ( 3H, m), 7.1-7.4 (8H, m). MS m / z: 523 (M + 1). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-hydroxymethyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-105) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-hydroxymethyl-1, 2,3,4-tetrahydro was prepared -quinolin-4-yl] -propionamide from 4- [(4-chloro-phenyl) -propionyl-amino] -1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinoline- 2-ylmethyl ester of (+) - cis-propionic acid using the saponification conditions used in the synthesis of (+) - cis- [4- [(4-chloro-phenyl) -propionyl-amino] -1 acid - (4-fluoro-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-6-yloxy] -acetic. X H NMR (CDCl 3) d: 1.1 (3 H, t), 1.3 (1 H, m), 1.8 (1 H, m), 2.1 (2 H, m), 3.4 (1 H, t ), 3.6 (2H, m), 4.2 (1H, m), 6.2 (1H, ra), 6.4 (1H, d), 6.7 (2H, t), 6.8 -7.0 (5H, m), 7.1-7.3 (4H, m). MS m / z: 367 (M-99). (±) -Cis-N- (4-chloro-phenyl) -N- [2-diethylaminomethyl-1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-106) (+) - cis-N- (4-chloro-phenyl) -N- [2-diethylaminomethyl-1- (4-fluoro-benzoyl) - 1, 2, 3, 4-tetrahydro was manufactured -quinolin-4-yl] -propionamide following general procedure B, replacing acetaldehyde with diethylamino-acetaldehyde, 4-dimethylaminobenzoyl chloride with 4-fluorobenzoyl chloride and propionyl chloride with acetyl chloride.
¾ RM (CDCI3) d: 0.8 (6H, m), 1.1 (3H, t), 1.1 (1H, m), 1.8 (2H, m), 2.2-2.5 (6H, m), 2.6 (1H, m), 4.8 (1H, m), 5.7 (1H, m), 6.4 (1H, d), 6.9 (3H, m) , 7.1-7.4 (8H, m). MS m / z: 523 (M + 2). (±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methoxymethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] - propionamide (B-107) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methoxymethyl-1, 2,3,4-tetrahydro was prepared -quinolin-4-yl] -propionamide following general procedure B, substituting acetaldehyde for methoxyacetaldehyde, 4-dimethylamino-benzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.1 (3 H, t), 1.3 (1 H, m), 1.8 (1 H, m), 2.1 (1 H, m), 3.4 (4 H, m ), 3.6 (2H, m), 4.2 (1H, m), 6.3 (1H, m), 6.5 (1H, d), 6.7 (1H, m), 6.8 -7.0 (4H, m), 7.1-7.4 (6H, m). MS m / z: 381 (M-99). (+) -Cis-N- (4-chloro-phenyl) -iV- [1- (4-fluoro-benzoyl) -2-phenyl-1,2,3,4-tetrahydro-quinolin-4-yl] - propionamide (B-108) (±) -cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-phenyl-1, 2, 3, 4-tetrahydro was manufactured -quinolin-4-yl] -propionamide following general procedure B, substituting acetaldehyde for benzaldehyde, 4-dimethylaminobenzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride. XH NMR (CDCl 3) d: 1.1-1.2 (3H, m), 1.2-1.4 (1H, m), 2.2-2.4 (2H, m), 2.4- 2.6 (1H, m), 5.6 (1H, t), 5.8 (1H, m), 6.6 (1H, d), 6.8 (2H, m), 7.0 (1H , m), 7.2-7.4 (13 H, m). MS m / z: 513 (M + 1).
(±) -Cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-109) (±) - cis-N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -6-methoxy-2-trifluoromethyl-1 was prepared , 2,3,4-tetrahydro-quinolin-4-yl] -propionamide following general procedure B, substituting N- (vinylcarbamic acid) benzyl ester for N- (4-chloro-phenyl) -N-vinyl-propionamide and acetaldehyde for trifluoroacetaldehyde in the synthesis of 11 and 4-dimethylaminobenzoyl chloride by 4-fluorobenzoyl chloride and propionyl chloride by acetyl chloride. XH NMR (CDC13) d: 1.1-1.2 (3H, m), 1.6 (1H, a), 2.2-2.4 (3H, m), 3.8 (3H, s) , 5.5 (1H, m), 5.6 (1H, m), 6.5 (1H, s), 6.8 (1H, s), 6.9 (2H, t), 7.1 - 7.3 (4H, m), 7.4 (2H, d). MS m / z: 535 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [6-methoxy-1- (3-methoxy-benzoyl) -2-trifluoromethyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -propionamide (B-110) (±) -cis-N- (4-chloro-phenyl) -N- [6-methoxy-1- ( 3-methoxy-benzoyl) -2-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide following the procedure for the synthesis of (+) - N- (4-chloro-phenyl) - ? - [1- (4-Fluoro-benzoyl) -6-methoxy-2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide, substituting 4-fluorobenzoyl chloride for chloride 2-furoílo. X H NMR (CDCl 3) d: 1.1-1.2 (3 H, m), 1.6 (1 H, a), 2.2 -2.4 (3 H, m), 3.7 (3 H, s) , 3.8 (3H, s), 5.5 (1H, m), 5.6 (1H, m), 6.5 (2H, m), 6.6 (1H, m), 6.8 ( 3H, m), 7.1 (1H, t), 7.2 (2H, d), 7.4 (2H, d).
S m / z: 547 (M + l). (+) -Cis-N- (4-chloro-phenyl) -N- [1- (furan-2-carbonyl) -6-methoxy-2-trifluoromethyl-1, 2,3,4-tetrahydro-quinolin-4 -yl] -propionamide (B-III) (±) -cis-N- (4-chloro-phenyl) -N- [1- (furan-2-carbonyl) -6-methoxy-2-trifluoromethyl-1 was made , 2,3, 4-tetrahydro-quinolin-4-yl] -propionamide propionaraide following the procedure for the synthesis of (±) - c sN- (4-chloro-phenyl) -N- [1- (4-fluoro- benzoyl) -6-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -propionamide, substituting 4-fluorobenzoyl chloride for 2-furoyl chloride. XH NMR (CDC13) d: 1.1-1.2 (3 H, m), 1.6 (1H, a), 2.2 -2.4 (3H, m), 3.8 (3H, s) ), 5.4 (2H, m), 6.0 (1H, m), 6.3 (1H, m), 6.8 (1H, m), 6.9 (1H, s), 7.0 (1H, m), 7.2 (2H, m), 7.4 (3H, m). MS m / z: 507 (M + 1). (+) -Cis-N- [2-benzyl-1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -IV- (4-chloro-phenyl) - propionamide (B-112) (±) - cis-N- [2-benzyl-1- (4-fluoro-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N- was made (4-chloro-phenyl) -propionamide following general procedure B, substituting acetaldehyde for phenylacetaldehyde, 4-dimethylammonium benzoyl chloride for 4-fluorobenzoyl chloride and propionyl chloride for acetyl chloride. X H NMR (CDCl 3) d: 1.14 (3 H, t), 2.05-2.52 (5 H, m), 3.18 - 3.24 (1H, m), 4.89 - 4.93 (1H, m) 5.45 - 5.55 (1H, a), 6.46 (1H, d), 6, 83 - 7, 37 (16 H, m). MS m / z: 528 (M + 1). (+) -Cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1, 2, 3, 4-tetrahydro-quinolin-4 -yl] -acetamide (B-113) (±) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1 was manufactured , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure B, substituting 4-dimethylammonium benzoyl chloride for 3-methyl isoxazole-5-carbonyl chloride. Separated (±) - cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinoline -4-yl] -acetamide by chiral HPLC using a Chiralcel OD column and eluting with 90% hexane / isocratic 10% ethanol system, yielding (2i?, 4S) - y (2S, 4R) -cis-N- (4-chloro-phenyl) -N- [2-methyl-1- (3-methyl-isoxazole-5-carbonyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (B-) 42 and B-36, respectively) XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.2 (3H, s) , 2.3 (1H, m), 4.7 (1H, m), 5.4 (1H, m), 5.8 (1H, s), 6.8 (1H, d), 7.1- 7.4 (7H, m). S m / z: 424 [M + l). The compounds B-114-B-147 can be prepared by the schemes set forth in Schemes 13 and 14 and by the general procedures B and others described herein. Those skilled in the art will be able to recognize or ensure, using only routine experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 2: Compounds Derived from General Procedure B Scheme 13 á & j 2- (S) -terc-butoxycarbonylamino-propyl ester of methane sulphonic acid (16) To a room temperature solution of 5-2-amino-propan-1-ol (28.23 g, 0.375 mol) in ethyl acetate. ethyl ether (300 mL) was added BOC anhydride (86.13 g, 0.395 mol) dissolved in 30 mL of ethyl acetate via an addition funnel (exothermic). The solution became turbid and then transparent. The reaction mixture was stirred for about 30 minutes. Tetramethylethylenediamine (TMEDA) (59.6 ml, 0.395 mol) was added and the reaction mixture was cooled to about 0 ° C. Methanesulfonyl chloride (30.6 ml, 0.395 mol) was added to the reaction mixture over a period of 30 minutes. After stirring for 2.5 hours at 0 ° C, a white precipitate formed. The reaction mixture was filtered and the filtrate was concentrated to ¾ volume, poured into hexanes (800 ml) and stirred rapidly. The mixture was cooled in an ice bath for 2 h and then filtered to give 82 g (86%) of 2- (S) -tert-butoxycarbonylamino-propyl-methanesulfonic acid ester. 1 H NMR (300 MHz, CDCl 3) D 1.23 (d, 3 H), 1.44 (s, 9 H), 3.03 (s, 2 H), 3.96 (m, 1 H), 4.15 (dd, 1H), 4.23 (dd, 1H), 4.58 (br s, 1H). Tere-butyl ester of (S) - (2-cyano-l-methyl-ethyl) -carbamic acid (17) Sodium cyanide (48.92 g, 0.421 mol) was added to dimethylformamide (DMF) (420 ml) and the The mixture was stirred at 35 ° C for 30 minutes. Tetrabutylammonium bromide was added (5.22 g, 0.016 mol) and the reaction mixture was stirred for a further 2 h at 35 ° C. 2 - (S) - tert-butoxycarbonylamino-propyl ester of methanesulfonic acid (82.03 g, 0.324 mol) was added and the reaction mixture was stirred at 35 ° C overnight. An additional 5.22 g of tetrabutylammonium bromide (0.016 mol) was added and stirred overnight at 35 ° C. Then, the mixture was partitioned between 1200 ml of water and 1600 ml of ethyl acetate. The resulting organic and aqueous phases were separated and extracted sequentially 2 times with 800 ml of ethyl acetate. The combined extracts were washed 3 times with 500 ml of water and a saturated solution of sodium chloride in water. The organic phase was dried over magnesium sulfate, filtered and concentrated, yielding a solid with a yield of 84% tert-butyl ester of (S) - (2-cyano-l-methyl-ethyl) -carbamic acid. . (S) -3-amino-butyronitrile (18) To a solution of (S) - (2-cyano-1-methyl-ethyl) -carbamic acid tert-butyl ester (50.29 g, 0.273 mol) dissolved in THF (550 mL) methane sulphonic acid (44 mL, 0.682 mol) was added and stirred for 20 minutes. The reaction mixture was heated to 65 ° C for about 3 h (make sure the reaction is purged during this time). The mixture was allowed to cool to room temperature. The resulting solids were isolated by filtration, yielding the title compound. The solids were suspended in dichloromethane and 300 ml of sat. Na 2 CO 3. and the pH was adjusted to 13 with 6 M NaOH (-20 ml). Extract with 2 x 500 ml of dichloromethane. Combine the organic extracts and wash with a saturated solution of sodium chloride in water. The organic phase was dried over sodium sulfate, filtered and concentrated to give (S) -3-amino-butyronitrile in 64% yield. ¾ NMR (300 MHz, CDC13) D.1.23 (d, 3H), ..1.46 (sa, 2H), 2.34 (dd, 1H), 2.43 (dd, 1H), 3, 34 (sextuplete, 1H). (S) -3-Phenylamino-butyronitrile (19) (S) -3-amino-butyronitrile (2.51 g, 0.030 mol) was dissolved in 40 ml of DMF, phenylboronic acid (4.73 g, 0.degree. , 0389 mol), Cu (OAc) 2 (7.06 g, 0.0389 mol) and pyridine (6.29 ml, 0.077 mol) and the reaction was heated to 65 ° C open to the air until no material remained. Starting with LC S (It is very important that this reaction does not take place under an argon or nitrogen atmosphere, air is needed to catalyze the reaction, and the reaction should be stirred very vigorously to allow the air to mix with the reaction.) . When the starting material disappeared (-18 h), the reaction was allowed to cool to room temperature, poured into ethyl acetate and filtered. Wash the precipitate well with ethyl acetate. The filtrate is washed 2 times with H20 and dried over Na2SO4, filtered and concentrated. Isco chromatography (gradient of 100% hexane to 30% ethyl acetate / 70% hexane) yielded N-phenylnitrile in 2.13 g (41%) as a white solid. ¾ NMR (300 MHz, CDC13)? (..d, 3H), .2.61 (d, 2H), 3.64 (sa, 1H), 3.90 (sa, 1H), 6, SO (d, 2H), 6.77 (t, 1H), 7.18-7.26 (m, 2H) (S ) -3-Phenylamino-butyramide (20) To a solution of (S) -3-phenylamino-butyronitrile (6.06 g, 0.0378 mol) in toluene (150 ml) was added a cooled solution of conc. Sulfuric acid. . in H20 (20.12 mi H2S04 / 3 mi) - (The ratio of toluene to acid / H20 is very important and should be strictly controlled). Stir the biphasic mixture at room temperature for 0.5 h and warm to 35 ° C and stir for 22 h. The reaction was cooled to room temperature and quenched with 13 g of Na 2 CO 3 in water (slowly add a little foam). Separate the organic and the extract with 2 x EtOAc. Combine all organic extracts and wash the organic extracts with brine, dry over MgSO4, filter and concentrate, giving the desired product in 2.11 g (90%) X H NMR (300 MHz, CDCl 3) d: 1, ~ 29 (d , 3H), 2.40 (dd, 1H), 2.48 (dd, 1H), 3.73 (s a, 1H), 3.92 (sextuplet, 1H), 5.52 (s a, 1H), 6.00 (s a, 1H), 6.66 (d, 2H), 6.74 (t, 1H), 7.19 (m, 2H) (S) - (3-phenylamino-butyryl) -carbamic acid benzyl ester (21) A clean, dried and purged flask with gas nitrogen was charged with (S) -3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 mL) and the mixture was cooled to -10 ° C. Then, benzyl chloroformate (3.12 ml, 0.022 mmol) was added followed by the slow addition of 1.0 M lithium tert-butoxide in a THF solution (18 ml). The solution of tere-lithium peroxide was added at such a rate that the internal temperature was below 0 ° C. Fifteen minutes after the addition of the base was completed, the reaction (without starting material by TLC) was stopped by adding EtOAc (65 ml) and 1.0 M hydrochloric acid (10 ml). Then, the aqueous phase was basified with 1 N NaOH. The aqueous phase was extracted with 3 x EtOAc. The organic extracts were collected together and with a saturated aqueous solution of sodium chloride (130 ml). The phases were separated, the organic phase was dried (MgSO 4), filtered and concentrated. Flash chromatography using a Biotage system (10% EtOAc / 90% hexane to 20% EtOAc / 80% Hexane) afforded the title compound in 82% yield. ½ NMR (300 MHz, CDC13) d: 1, ~ 30 (d, 3H), 2.87 (dd, 1H), 3.04 (dd, 1H), 3.80 (sa, 1H), 4.02 (m, 1H), 5.17 (s, 2H), 6.62 (d, 2H), 6.73 (t, 1H), 7.17 (t, 2H), 7.37 (s, 5H) , 8.13 (sa, 1H). Benzyl Ester of (2S, 4R) - (2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -carbamic acid (22) A clean, dried flask was charged with benzyl ester of the acid (S) ) - (3-phenylamino-butyryl) -carbamic acid (0.821 g, 2.63 mmol) followed by reactive grade ethanol (20 mL) and cooled to -10 ° C. Sodium borohydride (0.070 g, 1.84 mmol) was added to the solution in one portion. Purging with nitrogen gas was maintained for 5 minutes. An aqueous solution 3.3 of magnesium chloride (0.561 g gCl2 | 6 H20 in 1.5 ml of water) was added at such a rate that the internal temperature did not exceed -5 ° C. When the addition was complete, the reaction solution was heated at 0 ° C for 30 min. The reaction was quenched with methylene chloride (10 mL) and a 1M solution of hydrochloric acid / citric acid (10.52 mL of 1N HC1 and 1.38 g of citric acid). This biphase was stirred at room temperature for six hours. The reaction mixture was diluted with ethyl acetate (200 ml) and neutralized with a sat. aqueous NaHCO 3 (pH = 10). The organic extracts were collected together, washed with a sat. NaCl, dried over Na2SO, filtered and concentrated. Flash chromatography using an Isco system (gradient of 100% hexane to 50% EtOAc / 50% hexane) afforded the title compound (0.733 g) · (91%) | XH NMR (300 MHz, CDC13) d: 7.38 (m, 5H), 7.17 (d, 1H), 7.02 (t, 1H), 6.68 (t, 1H, C6-H), 6.47 (d, 1H), , 17 (sa, 2H), 5.07 (m, 1H), 4.92 (d, 1H), 3.78 (sa, 1H), 3.57 (m, 1H), 2.30 (m, 1H), 1.47 (c, 1H), 1.21 (d, 3H). General Procedure C Scheme 15 (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (25) To a solution of (25, 4J?) - (2-methyl-1,2,3,4-tetrahydro-quinol in-4-yl) -carbamic acid benzyl ester (1.0 g, 3) , 38 mmol) in methylene chloride (50 ml) at room temperature was added diisopropylethylamine (650 μl, 3.72 mmol) followed by 4-fluorobenzoyl chloride. The reaction was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (75% hexanes hexanes / 25% ethyl acetate) to yield pure amide (720 mg, 51%). Benzyl ester of (2S, AR) - [1- (4-fluorobenzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -carbamic acid ester (720 mg, 1.73 g) was dissolved. mmol) in ethanol (30 ml). The vessel in which the resulting solution resided is evacuated and replenished with argon. A catalytic amount of Palladium on Carbon (10%) was added. The vessel was evacuated again and at this time it was again filled with hydrogen and stirred in a Parr bottle at 275,790 kPa (40 psi) of hydrogen. The reaction was complete after 4 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through Celite® and concentrated, yielding the crude amine.
To a solution of (2S, 4i?) - (-amino-2-methyl-3,4-dihydro-2H-quinol ind-1-yl) - (- fluoro-phenyl) -methanone (1.0 g, 3 g) , 5 mmol) in DMF (20 ml, dry) was added 4-chlorophenylboronic acid (1.1 g, 7.0 mmol), pyridine (850 μl, 10.5 mmol) and copper (II) acetate ( 1.27 g, 7.0 mmol). The heterogeneous green mixture was stirred open in the air for 1 h and then heated to 60 ° C and stirred overnight (14 h). Then, the mixture was cooled to rt and poured into stirred ethyl acetate rapidly (150 ml); solids were re-filtered by filtration through Celite®. The extracts were washed several times with water and then once with brine. Then, the extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (95% methylene chloride / 5% ethyl acetate) to yield the product aniline (250 mg, 18%) as a yellow oil. To a solution of (2S, 4R) - [4 - (4-chloro-phenylamino) -2-methyl-3,4-dihydro-2H-quinolin-1 -yl] - (4-f luoro-phenyl) -methanone (250 mg, 0.636 mmol) in methylene chloride (5 ml) was added diisopropylethylamine (120 μl, 0.70 mmol) followed by acetyl chloride (90 μl, 1.27 mmol). The mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. Sodium bicarbonate. aqueous and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (gradient of 25/75 hexanes / ethyl acetate) yielding N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-methyl -l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide pure (200 mg, 71%). ¾ NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, d), 2.3 (1H, m), 4.7 (1H, m ), 5.6 (1H, m), 6.5 (1H, d), 6, 7-7.0 (3H, m), 7, 1-7.4 (8H, m). MS m / z: 436 (M + 1). (2S, 4J2) - N- (4-chloro-phenyl) -iV- [2-methyl-1- (4-morpholin-4-yl-benzoyl) -1,2,3,4-tetrahydro-quinolin-4 -yl] -acetamide (C-1) (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1 - (4-morpholin-4-yl-benzoyl) was made -1,2,3, 4-tetrahydro-quinol in-4-i 1] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for bromobenzoyl chloride. Another elaboration was made to the morpholine following the same procedure as described for (±) -N- (4-chloro-phenyl) -N- [1- (4-fluoro-benzoyl) -2-met il-6- morphol in-4-il-1, 2,3,4-tetrahydro-quinolin-4-yl] -propionamide. XH NMR (CDC13) d: 1.13 (d, 3H), 1.22 (t, 1H), 2.03 (s, 3H), 2.29 (s, 1H), 3.31 (t, 4H) ), 3.80 (t, 4H), 4.75 (sextuplet, 1H), 5.61 (sa, 1H), 6.58 (d, 1H), 6.64 (d, 2H), 6.94 (t, 1H), 7.15 (d, 2H), 7.18 (t, 1H), 7.21 (d, 2H), 7.28-7.39 (m, 3H). MS m / z: 505, 4 (M + 1). (2S, 4R) -4- (4- {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenoxy) -butyric acid (C-2) (2S, 4R) -4 - (4 -. {4 - [Acetyl - (4-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carboni 1.}. -phenoxy) -butyric following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Further elaboration of the acid was carried out following the same procedure as described for (±) -4- (4- { 4- [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3 acid, 4-dihydro-2H-quinoline-1 -carbonyl-1.} - phenoxy) -butyric acid. X H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.1 (2 H, m), 2.3 (1 H, m ), 2.5 (2H, m), 3.9 (2H, m), 4.7 (1H, m), 5.6 (1H, m),), 6.5 (1H, d), 6 , 7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 522 (M + 2). (2S, 4J?) -N- (4-Chloro-phenyl) -N- [1- (4-dimethylamino-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide (C-3) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-dimet i-lamino-benzoyl) -2-methyl-l, 2,3, 4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-dimethylaminobenzoyl chloride. ?? NMR (300 MHz, CDCl 3) d: 1.14-1.33 (m, 4H), 2.13 (s, 3H), 2.24-2.39 (m, 1H), 2.94 (s, 6H), 4.75 (ddd, 1H), 5.61 (sa, 1H), 6.44 (d, 2H), 6.63 (d, 1H), 6.96 (dd, 1H), 7, 07-7.36 (m, 6H), 7.40 (d, 2H). MS m / z: 420 (M + 1). (2S, 4J¾) -IV- (4-Chloro-phenyl) -iV- [1- (4-isopropoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (C-4) was prepared (2S, 4i?) -N- (4-chloro-phenyl) -N- [1- (4-isopropoxy-benzoyl) -2-methyl -1,2,3,4- tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-isopropoxybenzoyl chloride. X H NMR (300 MHz, CDCl 3) d: 1.14 (d, 3 H), 1.23-1.31 (m, 7 H), 2.03 (s, 3 H), 2.23-2.35 ( m, 1H), 4.48 (sept., 1H), 4.74 (ddd, 1H), 5.61 (sa, 1H), 6.55 (d, 1H), 6.64 (d, 2H) , 6.92 (dd, 1H), 7.09-7.24 (m, 5H), 7.29 (d, 1H), 7.34-7.41 (m, 2H). MS m / z: 477 (M + 1). . { 2S, ÍR) - N- (4-Chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1,2,3, 4-tetrahydro- quinolin-4-yl] -acetamide (C-5) was prepared. { 2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pyridine-3-carbonyl) -1,2,3, 4-tetrahydro- quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 2-chloronicotinoyl chloride. Before removal of the benzyl carbamate, chloronicotinamide was converted to 2-morpholinonicotinamide as indicated below. A solution of (2S, 4i?) - [1 - (6-chloro-nicotinyl) -2-metyl-1,2,3,4-tetrahydro-quinolin-4-yl] - benzyl ester was dissolved. carbamic (525 mg, 1.20 mol) in morpholine (5 ml). The resulting solution was heated at 70 ° C overnight. After the reaction was complete (12 h), the solution was concentrated under reduced pressure; the crude residue was dissolved in ethyl acetate and washed with water and brine to remove the remaining morpholine. The extracts were dried over sodium sulfate, filtered and concentrated to yield crude morpholinonicotinate (639 mg,> 100%). The resulting product was taken to (2S, R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (6-morpholin-4-yl-pi-idine-3-carbonyl) -1 , 2,3,4-tetrahydro-quinolin-4-yl] -acetamide fully worked up as described in general procedure C. 1K NMR (300 MHz, CDC13) d: 1.11-1.22 (m, 4H ), 2.03 (s, 3H), 2.24-2.38 (m, 1 H), 3.48-3.56 (m, 4H), 3.74-3.80 (m, 4H) , 4.73 (ddd, 1H), 5.56 (sa, 1H), 6.30 (d, 1H), 6.66 (d, 1H), 7.02 (dd, 1H), 7.12 ( dd, 1H), 7.16-7.25 (m, 3H), 7.32 (d, 1H), 7.40 (d, 2H), 8.24 (sa, 1H). MS m / z: 505 (M + 1). (25, 4LR) -N- (4-Chloro-phenyl) -N- [1- (3-ethyl-isoxazole-5-carbonyl) -2-methyl-1,2,3-tetrahydro-quinoline-4 - il] -acetamide (C-6) was prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1 - (3-yl-isoxazole-5-carbonyl) -2-methyl- 1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethylisoxazolecarbonyl chloride. ¾ NMR (300 MHz, CDC13) d: 1.06-1.23 (m, 7 H), 2.02 (s, 3H), 2.21-2.37 (m, 1H), 2.52- 2.66 (m, 2H), 4.72 (ddd, 1H), 5.34-5.56 (sa, 1H), 5.88 (s, 1H), 6.80 (d, 1H), 7 , 11 (dd, 1H), 7.20 (d, 2H), 7.28-7.43 (m, 4H). MS m / z: 438 (M + 1). (2S, 4i¾) -N- [1- (3-Benzyl-isoxazole-5-carbonyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro) phenyl) -acetamide (C-7) was prepared (2S, 4R) -N- [1- (3-benzyl-isoxazol-5-carbonyl) -2-methyl-l, 2,3,4-tetrahydro-quinolin -4-yl] -N- (4-chloro-phenyl) -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-benzylisoxazolecarbonyl chloride. X H NMR (300 MHz, CDCl 3) d: 1, 06-1.43 (m, 4H), 2.01 (s, 3H), 2.16-2.35 (m, 1H), 3.81-4 , 01 (m, 2H), 4.70 (ddd, 1H), 5.40 (sa, 1H), 5.83 (s, 1H), 6.75 (d, 1H), 7.02 (dd, 1H), 7.10 (m, d, 2H), 7.14-7.22 (m, 2H), 7.22-7.34 (m, 5H), 7.38 (d, 2H). MS m / z: 500 (M + 1). (2S, 4J?) -N- (4-Chloro-phenyl) -N- [1- (3-methoxymethyl-isoxazole-5-carbonyl) -2-methyl-1,2,3-tetrahydro-quinoline-4 -yl] -acetamide (C-8) Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (3-methoxymethyl-isoxazole-5-carbonyl) -2-methyl-1 , 2,3-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for it by 3-methoxymethyl isoxazolecarbonyl ether chloride. ¾ NMR (300 MHz, CDCl 3) d: 1.11-1.24 (m, 4H), 2.02 (s, 3H), 2.22-2.39 (m, 1H), 3.28 (s, 3H), 4.42 (s, 2H), 4.73 (ddd, 1H), 5.46 (ss, 1H) ), 6.09 (s, 1H), 6.79 (d, 1H), 7.10 (d, 1H), 7.10 (d, 2H), 7.27-7.42 (m, 4H) . MS m / z: 454 (M + 1).
Ethyl ester of (2S, 4J¾) -4- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1- carbonyl) -phenoxy) -piperidine-1-carboxylic acid (C-9) (2S, 41?) -4 - (4-. {4 - [acetyl- (4-chloro-phenyl) ethyl ester was prepared ) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.} - phenoxy) -piperidine-1-carboxylic acid following the general procedure C, substituting 4-fluorobenzoyl chloride for ethyl ester of the 4- (4-chlorocarbonyl-enoxy) -piperidine-l-carboxylic acid. 1 H NMR (CDC13) d: 1.1 (3 H, d), 1.1 (1 H, m), 1.2 (3 H, t), 1.7 (2H, m), 1.9 (2H, m), 2.0 (3H, s), 2.3 (1H, m), 3.3 (2H, m), 3.7 (2H , m), 4.1 (2H, c), 4.4 (1H, m), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6 , 7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 590 (M). (2S, 4R) -2- (4-. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2J-quinoline-1 -carbonyl}. phenoxy) -acetamide (C-10) (2S, 41?) -2 - (4 -. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3, 4 was made -dihydro-2H-quinoline-1-carbonyl.}. -phenoxy) -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) - 2-methyl-l, 2,3, -tetrahydro-quinolin-4-yl] -acetamide. Prepared (2S, 4R) -N- (-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration of the amide was carried out following the same procedure as described for (+) - N - [1- (4-carbamoylmethoxy-benzoyl) -2-methyl-l, 2,3, -tetrahydro-quinolin-4- il] -N-phenyl-propionamide.
X H NMR (CDCl 3) d: 1.1 (3 H, m), 1.8 (1 H, s), 2.0 (3 H, s), 2.3 (1 H, m), 4.4 (2 H, s ), 4.7 (1H, m), 5.6 (1H, a), 5.9 (2H, sa) 6.5 (2H, d), 6.7 (2H, d), 6.9 ( 1H, t), 7.2-7.4 (7H, m). MS m / z: 492 (+ l). (2S, 4 £) -N- (4-Chloro-phenyl) -J7-. { 2-methyl-l - [4- (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (C-11) (2S, 4i?) -N- (4-chloro-phenyl) -N- was manufactured. { 2-met il-1 - [4 - (2-morphin-4-yl-ethoxy) -benzoyl] -1,2,4,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3,4-tetrahydro-quinol in -4-yl] -acetamide. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol in-4- il] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration of morpholine was carried out following the same procedure as described for (±) -N-. { 2-methyl-1 - [4 - (2-morpholin-4-yl-ethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -N-phenyl-propionamide. X H NMR (CDCl 3) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1H, m), 2.6 (4H, m), 2.8 (2H, m), 3.7 (4H, m), 4.1 (2H, m), 4.7 (1H , m), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d). MS m / z: 549 (M + 2). (2S, 42?) - (4. {4- [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}. - phenoxy) -acetic (C-13) Acid was manufactured. { 2S, 4i?) - (4 - { 4 - [acetyl - (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinol ina-1 -carbonyl.} - phenoxy) -acetic was made from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4- tetrahydro-quinolin-4-yl] -acetamide. Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-me oxy-benzoyl) -2-methyl-1,2,3-tetrahydro-quinolin-4-yl ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Another elaboration of the acid was carried out following the same procedure as described for acid. { (+) -4- [2-methyl -4 - (phenyl-propionyl-amino) -3, 4-dihydro-2-f-quinoline-1-carbonyl] -phenoxy} -acetic 1 H NMR (CDC13) d: 1.1 (3 H, d), 1.1 (1 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.3 (2 H, s ), 4.6 (1H, m), 5.6 (1H, m), 6.4-6.9 (5H, m), 7.0-7.4 (7H, m). MS m / z: 494 (M + 2). . { 2S, iR) - N- (4-Chloro-phenyl) -V-. { 2-methyl-l- [4- (1-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (C-14) (2S, 4R) -N- (4-chloro-phenyl) -N- was made. { 2-met il-1 - [4 - (1-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, -tetrahydro-quinolin-4 -yl] -acetamide. Prepared (2S, 4R) -N- (4-Chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl ] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. Further elaboration of the tetrazole was carried out following the same procedure as described for (±) -N- (4-chloro-phenyl) -N-. { 2-met il-1 - [4- (1H-tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinol in 4-yl} -propionamide. ¾ NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 4.8 (1H, m ), 5.2 (2H, dd), 5.6 (1H, m), 6.4 (1H, m), 6.5 (1H, d), 7.0 (2H, m), 7.1 -7.4 (8H, m).
MS m / z: 517 (M + 1). (2S, 4i¾) -N-. { 1- [4- (1-Acetyl-piperidin-4-yloxy) -benzoyl] -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl} -N- (4-chloro-phenyl) -acetamide (C-15) was prepared (2S, 4J?) -JV-. { l- [4- (1-Acetyl-piperidin-4-yloxy) -benzoyl] -2-methyl-l, 2,3,4-tetrahydro-quinolin-4-yl} -N- (4-Chloro-phenyl) -acetamide from (2S, 4R) -4 - (4- (4- [Acetyl- (4-chlorophenyl) -amino] -2-methyl) ethyl ester -3,4-dihydro-2H-quinoline-1-carbonyl.] -phenoxy) -piperidine-1-carboxylic acid, followed by removal of ethoxycarbamate using basic hydrolysis and then acetylation. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 1.6-2.1 (4H, m), 2.0 (6H, s), 2.3 (1H, m), 3.4 ( 1H, m), 3.5-3.8 (3H, m), 4.4 (1H, m), 4.7 (1H, m), 5.6 (1H, m), 6.5 (1H , d), 6.7 (2H, d), 6.9 (1H, t), 7.1-7.3 (7H, m), 7.4 (1H, d) MS m / z: 560 (M + l). (2 £, 4 £) - N- (4-Chloro-phenyl) -N-. {2-methyl-1- [4- (pyridin-4-ylmethoxy) -benzoyl] -1 , 2, 3, 4-tetrahydro-quinolin-4-yl.}. -acetamide (C-16) { 2S, 4R) -N- (4-chloro-phenyl) -N- was made. { 2-methyl-1 - [4 - (pyridin-4-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide (2S, 4R) -N- (4-chloro-phenyl) -N-. { 2-met il-1 - [4 - (1 H -tetrazol-5-ylmethoxy) -benzoyl] -1,2,3,4-tetrahydro-quinolin-4-yl} -acetamide was manufactured from (2S, 4R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro- quinolin-4-yl] -acetamide. (2S, 4i?) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzole-1) -2-methyl-1,2,4,4-tetrahydro-quinoline-4 was prepared -yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. [2S, R) -N- (4-chloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol in-4- was dissolved il] -acetamide in dichloromethane and a solution of BBr3 (1.0 M in dichloromethane, 10 ml) was added thereto; the reaction was allowed to stir at room temperature until no starting material remained. The reaction was carefully washed with sat. NaHCO 3. and brine. The organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography Biotage using 100% EtOAc to give a white solid. The phenol was dissolved in DMF (5 ml) at room temperature. Sodium hydride (60% in oil) was added and the mixture was allowed to stir for 30 min. 4-Bromomethyl-pyridine was added and the reaction was allowed to stir overnight. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO, filtered and concentrated. The crude residue was purified by chromatography on silica gel (gradient 2/98 methanol / dichloromethane- 5/95 methanol / dichloromethane) to produce the product. XE NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 4.7 (1H, m ), 5.0 (2H, s), 5.6 (1H, m), 6.5 (1H, d), 6.7 (2H, d), 6.9 (1H, t), 7.0 -7.4 (10H, m), 8.6 (2H, d).
MS m / z: 526 (M + 1). (2S, 4J?) -4- (3. {4 - [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl acid} - phenoxy) -butyric (C-17) Acid (2S, 4i¾) -4 - (3 -. {4 - [acetyl - (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -carbonyl was prepared .).-phenoxy) -butyric following general procedure C, substituting 4-fluorobenzoyl chloride for 3-methoxybenzoyl chloride. Further processing of the acid was carried out following the same procedure as described for (±) -4- (4- { 4- [(4-chloro-phenyl) -propionyl-amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.] - phenoxy) -butyric acid. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 1.8-2.0 (2H, m), 2.0 (3H, s), 2.3 (1H, m), 2.4 (2H, m), 3.8 (2H, m), 4.8 (1H, m), 5.7 (1H, m), 6.4 (1H, m) , 6.5 (1H, d), 6.8 (1H, m), 7.0 (1H, t), 7.1-7.4 (7H, m), 7.5 (1H, m). MS m / z: 521 (+ l). (2S, 4R) -iV- (4-Chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide ( C-18) Prepared (2S, 4i?) -N- (4-chloro-phenyl) -N- [1- (4-hydroxy-benzoyl) -2-methyl-L, 2, 3, 4-tetrahydro- quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-methoxybenzoyl chloride. Another elaboration of the phenol was carried out following the same procedure as described for (±) -N- [1- (4-hydroxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4- il] -N-phenyl-propionamide. ¾ NMR (CDCl 3) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 4.7 (1H, m ), 5.6 (1H, m), 6.4 (2H, d), 6.5 (1H, d), 6.9 (3H, m), 7.1-7.3 (4H, m) , 7.4 (2H, m), 8.0 (1H, a). MS m / z: 435 (M + 1). Ethyl ester (23, 41?) -4 - (4 - { 4 - [Acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1 -cnyl.}. -phenyl) -piperidine-1-cxylic acid (C-19). (2S, 4i?) -4- (4-. {4- [Acetyl- (4-chloro- phenyl) -amino] -2-methyl-3, 4-dihydro-2H-quinoline-1-cnyl.} - phenyl) -piperidine-1-cxylic acid following the general procedure C, substituting -fluorobenzoyl chloride for ethyl ester of the 4- (4-chlorocnyl-phenyl) -iperidine-1-cxylic acid. X H NMR (CDCl 3) d: 1.1 (4 H, m), 1.3 (3 H, m), 1.5 (2 H, m), 1.7 (2 H, m), 2.0 (3 H, s ), 2.3 (1H, m), 2.6 (1H, m), 2.8 (2H, t), 4.1 (2H, m), 4.2 (2H, m), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.0 (2H, d), 7.1 (2H, d) , 7.3 (5H, m), 7.4 (2H, m). MS m / z: 474 (M + 1). (2S, 4 £) -N- (4-Chloro-phenyl) -N- [1- (3-ethoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide (C-20) [2S, 4R) -N- (4-chloro-phenyl) -N- [1- (3-ethoxy-benzoyl) -2-methyl-1, 2, 3, 4- was prepared tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethoxybenzoyl chloride. X H NMR (CDCl 3) d: 1.2 (3 H, m), 1.3 (4 H, m), 2.0 (3 H, s), 2. 2 (1H, m), 3.9 (2H, m), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.7 (1H, d) ), 6.8 (2H, m), 6.9 (1H, m), 7.0 (1H, m), 7.1- 7.3 (4H, m), 7.4 (2H, d). MS m / z: 463 (M + 1). Ethyl ester of (2S, 4R) - (4 -. {4 - [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2-yl-quinoline-1-carbonyl ester}-phenyl) -carbamic acid (C-22) (2S, 4R) - (4 -. {4 - [acetyl - (4-chloro-phenyl) -amino] -2-methyl- ethyl ester was prepared. 3,4-dihydro-2H-quinoline-1-carbonyl.) - phenyl) -carbamic following general procedure C, substituting 4-fluorobenzoyl chloride for (4-chlorocarbonyl-phenyl) -carbamic acid ethyl ester.
X H NMR (CDCl 3) d: 1.1 (3 H, m), 1.3 (4 H, m), 2.0 (3 H, s), 2.3 (1 H, m), 4.2 (2 H, m ), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.1-7.3 (8H, m ), 7.4 (2H, d). MS m / z: 506 (M + 1). (2S, 4 £) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-oxazol-5-yl-benzoyl) -1,2,3,4-tetrahydro-quinoline- 4-yl] -acetamide (C-24) was prepared (2S, 4i?) -N- (4-chloro-phenyl) -N- [2-methyl-1- (4-oxazol-5-yl-benzol 1 ) -1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-oxazol-5-yl-benzoyl chloride. X H NMR (CDCl 3) d: 1.2 (3 H, m), 1.3 (1 H, m), 2.1 (3 H, s), 2.3 (1 H, m), 4.8 (1 H, m ), 5.6 (1H, a), 6.5 (1H, d), 6.9 (1H, m), 7.1-7.3 (8H, m), 7.4 (1H, d) , 7.5 (2 H, d), 7.9 (1H, s). MS m / z: 486 (M + 1). (2S, 4J?) -N- (3,4-Dichloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4- il] -acetamide (C-25) (2S, 4R) -N- (3,4-dichloro-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2, 3,4-tetrahydro-quinolin-4-yl] -acetamide following general procedure C, substituting 4-chlorophenylboronic acid for 3,4-dichlorophenylboronic acid and 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride. ¾ NMR (CDCl 3) d: 1.2 (3H, m), 1.3 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.7 (3H, s ), 4.8 (1H, m), 5.6 (1H, a), 6.6 (1H, d), 6.7 (2H, d), 7.0 (1H, m), 7.2 (3H, m), 7.3 (2H, d), 7.4 (1H, s), 7.5 (1H, d). MS m / z: 483 (M + 1). (2S, 4R) -N- (2, 3-Dihydro-benzo [1,4] dioxin-6-yl) -N- [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3 , 4-tetrahydro-quinolin-4-yl] -acetamide (C-26) It was manufactured (2S, 4R) -N- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -N- [1- (4-methoxy-benzoyl) -2-me-il-l, 2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting acid-chlorophenylboronic acid for 2,3- dihydro-benzo [1,4] dioxin-6-carboxylic acid and 4-fluorobenzoyl chloride per 4-methoxyphenylbenzoyl chloride. XH NMR (CDC13) d: 1.2 (3H, m), 1.3 (1H, m), 2.0 (3H, s), 2.4 (1H, m), 3.7 (3H, s) ), 4.3 (4H, s), 4.8 (1H, m), 5.6 (1H, a), 6.5 (1H, d), 6.68 (2H, d), 6.7 -6.9 (3H, m), 7.10-7.3 (5H, m). MS m / z: 474 (M + 2). (2S, 42¾) -N- [1- (4-Methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -iV-p-tolyl-acetamide (C-) 27) (2S, 4R) -N- [1- (4-Methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-p-tolyl-acetamide was prepared following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-toluenoboric acid. XH NMR (CDCl 3) d: 1.15 (3H, d; overlap 1H, t), 2.01 (3H, s), 2.33-2.35 (overlap 1H, m, 1H, s), 3, 73 (3H, s), 4.70 (1H, m), 5.65 (1H, m), 6.50 (1H, d), 6.68 (2 x 1H, d), 6.95 (1H , t), 7.00-7.40 (8H, m). MS m / z: 429 (M + 1). (2S, 4J¾) -N- (4-Chloro-phenyl) -N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1, 2, 3, 4-tetrahydro-quinoline-4 - il] -acetamide (C-28) Prepared (2S, 4R) -N- (4-chloro-phenyl) -N- [2-methyl-1- (4-pyrrolidin-1-yl-benzoyl) -1 , 2,3,4-ehydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-pyrrolidin-1-yl-benzoyl chloride for 4-fluorobenzoyl chloride.
?? NMR (CDC13) d: 1.11-1.15 (4? Ra), 1.94-1.98 (4? M), 2.03 (3H, s), 2.24-2.34 (1 HOUR, m), 3.21-3.25 (4H, m), 4.68-4.75 (1H, m), 5.61-5.65 (1H, a), 6.30 (2H, d ), 6.63 (1H, d), 6.92-7, 52 (9H, m). MS m / z: 488 (M + 1). (2S, 4R) -iV- (4-Chloro-phenyl) -N- [1- (1-isopropyl-1H-benzotriazole-5-carbonyl) -2-methyl-1, 2,3, 4-tetrahydro-quinoline -4-yl] -acetamide (C-29) (2S, AR) -N- (4-chloro-phenyl) -N- [1- (1-isopropyl-1H-benzotriazole-5-carbonyl) -2 was made -methyl-l, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 1-isopropyl-lH-benzotriazole-5-carbonyl chloride. ? NMR (CDCl 3) d: 1.19-1.27 (4H, m), 1.68 (6H, d), 2.04 (3H, s), 2.30-2.40 (1H, m), 4.83 (1H, c), 4.98 (1H, c) 5.45-5.55 (1H, a), 6.48 (1H, d), 6.83 (1H, t), 7, 10-7.41 (8H, m), 8, 13 (1H, a). MS m / z: 503 (M + 1). (2S, 4J2) -N- (4-Chloro-phenyl) -N-. { l- [4- (1-Hydroxy-l-methyl-ethyl) -benzoyl] -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl} -acetamide (C-30) was prepared. { 2S, AR) -N- (4-chloro-phenyl) -N-. { l- [4- (1-Hydroxy-l-methyl-ethyl) -benzoyl] -2-methyl-1,2,4,4-tetrahydro-quinolin-4-yl} -acetamide from. { 2S, R) -N- [1- (4-acetyl-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- (4-chloro-phenyl) -acetamide . It was dissolved (2S, R) -N- [1- (4-acetyl-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl] -N- (4-chloro- phenyl) -acetamide (112 mg, 124 mmol) in THF (5 mL) and cooled to 0 ° C. Methylmagnesium bromide (1.4 M in ether, 2 mL, 2.4 mmol) was added and the mixture was stirred at 0 ° C for 2 h. The reaction was warmed to rt and stirred for a further 2 h. The reaction was poured into saturated aqueous ammonium chloride. The phases were separated and the aqueous phase was extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude alcohol was purified by chromatography on silica gel yielding the pure product (20 mg, 24%). XH NMR (CDC13) d: 1.12-1.21 (4H, m), 1.48 (6H, d), 2.02 (3H, s), 2.25-2.34 (1H, m) , 4.70-4.80 (1H, m), 5.45-5.54 (1H, a), 6.50 (1H, d), 6.88 (1H, t), 7.11-7 , 38 (10H, m). MS m / z: 478 (M + 1). (2S, 4J2) -N- (4-Chloro-phenyl) -N- [1- (3-ethoxy-isoxazole-5-carbonyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinoline-4 -yl] -acetamide (C-31) was prepared (2S, 4J¾) -N- (4-chloro-phenyl) -jV- [1- (3-ethoxy-isoxazole-5-carbonyl) -2-methyl-1 , 2,3, 4- tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 3-ethoxy-isoxazole-5-carbonyl chloride. ? NMR (CDCl 3) d: 1.16 (3H, d), 1.33 (3H, t), 1.69 (1H, sa), 2.00 (3H, s), 2.21-2.38 ( 1H, m), 4.21 (2H, c), 4.66-4.73 (1H, m), 5.65 (1H, s), 6.86 (1H, d), 7.13-7 , 39 (8H, m). MS m / z: 454 (M). Acid (2S, 422) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl} .-phenyl) -propionic (C-32) (2S, 4i?) -3 - (4 -. {4 - [Acetyl - (4-chloro-phenyl) -amino] -2-methyl-3) acid was prepared , 4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -propionic acid from (2S, 4J2) -3- (4- (4- [acetyl- (4-chloro-phenyl) -amino] ] -2-methyl-3, 4-dihydro-2H-quinoline-1-carbonyl.} - phenyl) -acrylic acid (2S, 4R) -3- (4-. {4- [acetyl- (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro-2-f-quinoline-1 -carbonyl.} - phenyl) -acrylic (50 mg, 0.102 mmol) in EtOH (2 ml) and CH2Cl2 (10 drops for solubility) to Pd-C (10%, approximately 50 mg) and to 1 atm of H2 gas After 1 hour, the mixture was filtered, concentrated and chromatographed on silica gel (from 2% MeOH in EtOAc to 10% MeOH in EtOAc), yielding the title compound (50 mg, 99%). LE NMR (CDC13 300 MHz) d 1.09 (3H, d), 1.1 7-1.18 (1H, m), 2.00 (3H, s), 2.20-2.35 (1H, m), 2.46-2.60 (2H, m), 2.80- 2.90 (2H, m), 4.65-4.80 (1H, m), 5.40-5.71 (1H, m), 6.48 (1H, d), 6.89 (1H, t), 7, C (2H, d), 7.12 (2H, d), 7.20-7.48 (5H, m), 7.72 (1H, d). MS m / z: 322 (M-C8H7NO). Acid (2S, 42?) -3- (4- { 4- [Acetyl- (4-chlorophenyl) -amino] -2-methyl-3, 4-dihydro-2-yl-quinoline-1-carbonyl} phenyl) -acrylic (C-33) (2S, 4R) -3 - (-. {4 - [acetyl - (-chloro-phenyl) -amino] -2-methyl-3, 4-dihydro) was prepared -2H-quinoline-1-carbonyl.} -phenyl) -acrylic following general procedure C, substituting 4 - f luorobenzoyl chloride for methyl 3- (4-chlorocarbonyl-phenyl) -acrylic acid. The ester was hydrolyzed as indicated below. To a solution of (2S, 4J?) -3 - (4 -. {4 - [acetyl - (4-chloro-phenyl) -amino] -2-methyl-3,4-dihydro) methyl ester. -2H-quinoline-1-carbonyl.} -phenyl) -acrylic acid (112 mg, 0.239 mmol) in THF / MeOH (2 mL, 2 mL) was added LiOH (4 mL, 1.0 M in H20). After the starting unit was consumed (1 hour), the mixture was neutralized with HC1 aq. (1.0 M), partitioned with EtOAc (10 mL) and separated. The organic phase was separated and concentrated, whereby the resulting oil was chromatographed on silica gel (2% eOH in EtOAc to 10% MeOH in EtOAc) to yield the title compound (110 mg, 99% ). X H NMR (MeOD, 300 MHz) d 0.85-0.95 (1H, ra), 1.12 (3H, d), 2.04 (3H, s), 2.40-2.53 (1H, m), 4.70-4.80 (1H, m), 5.50-5.71 (1H, m), 6.4d (1H, d), 6.57 (1H, d), 6.96. (1H, t), 7.20-7.55 (8H, m), 7.60 (2H, d), 7.81 (1H, d). MS m / z: 320 (-C8H7NO). (2S, R) -N- [1- (4-ethoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- (4-methoxy-phenyl) - acetamide (C-34) was prepared (2 S, R) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N - (4-methoxy-phenyl) -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid. ?? NMR (CDC13 300 MHz) d 1.12 (3H, d), 1.20-1.23 (1H, m), 2.09 (3H, s), 2.30-2.42 (1H, m), 3.71 (3H, s), 3.81 (3H, s) 4.70-4.81 (1H, m) ), 5.50-5.80 (1H, m), 6.52 (1H, d), 6.67 (2H, d), 6.80-6.94 (4H, m), 7.10- 7.40 (5H, m). MS m / z: 280 (M- C9H10NO2). . { 2S, 4R) -N- (4-Isopropyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (C-35) Prepared (2S, 4?) -IV- (4-isopropyl-Eeni 1) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4- etrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4-isopropylphenylboronic acid. X H NMR (CDCl 3 300 MHz) d 1.21 (6H, d), 1.20-1.23 (1H, m), 1.23 (3H, d), 2.09 (3H, s), 2, 30-2.42 (1H, m), 2.80-2.95 (1H, m), 3.74 (3H, s), 4.65-4.83 (1H, m), 5.50- 5.80 (1H, m), 6.53 (1H, d), 6.67 (2H, d), 6.72 (2H, d), 6.92 (1H, t), 7.02-7 , 12 (3H, m), 7.21 (2H, d), 7.38 (1H, d). MS m / z: 280 (M- CxlHi4NO). (2S, 4R) -N- (-Bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (C-36) (2S, 4R) -N- (4-bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro- quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenic acid Ibórico for 4-bromo-phenylboronic acid. XH NMR (CDC13 300 Hz) d 1.12 (3H, d), 1.20-1.24 (1H, m), 2.05 (3H, s), 2.20-2.38 (1H, m ), 3.72 (3H, s), 4.66-4.81 (1H, m), 5.50-5.75 (1H, m), 6.52 (1H, d), 6.67 ( 2H, d), 6.92 (1H, t), 7.10-7.18 (5H, m), 7.26 (1H, t), 7.48-7.58 (2H, m). MS m / z: 493 (M + 1). Acid (2S, 4J2) -4-. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid (C-37). (2S, 4R) -4-. { acet il - [1 - (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic acid from methyl ester of the acid (25,4i¾) -4-. { ace i 1 - [1 - (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic Methyl ester of (2S, 4 £) -4- acid was prepared. { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} -benzoic following general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for methyl ester of 4-phenoic acid. The methyl ester of the acid (2S, 4í?) -4 -. { acetyl- [1- (-methoxybenzoyl-1) -2-met i 1, 1, 2, 3, 4-tetrahydro-quir.ol in- 4-yl] -amino} -benzoic acid was converted using the following procedure. To a solution of 4-methyl ester. { acetyl - [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino) -benzoic acid (10 mg, 0.038 mmol) in 4 ml of methanol 100 mg of K2C03 (0.72 mmol, in 0.5 ml of water) was added. The resulting reaction mixture was stirred at room temperature overnight. The methanol was removed in vacuo. 1 M HC1 was added until the mixture became acidic. Dichloromethane (20 ml) and 5 ml of water were added. The organic phase was dried with magnesium sulfate. The dichloromethane was removed in vacuo to give the title compound (15 mg, 86%) ¾ NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 3.8 (3H, s), 4.8 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6, 6 (2H, d), 6.9 (1H, t), 7.1-7.4 (6H, m), 8.1 (2H, d). MS m / z: 460 (M + 2). (25, 42?) -N- (3-Aminomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (C-38) was prepared (25, 4i?) -IV- (3-aminomethyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl- 1, 2, 3, 4 - tetrahydro-quinolin-4-yl] -acetamide from (2 S, AR) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4 -tetrahydro-quinolin-4-yl] -acetamide. Prepared (2S, 4J?) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline-4- il] -acetamide following the conventional procedure C, substituting 4-fluorobenzoyl chloride for 3-cyanophenylboronic acid. To a mixture of (2S, 4J¾) -N- (3-cyano-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinoline-4 -yl] -acetamide (48 mg, 0.11 mmol) in 2 ml of ethanol was added cobalt chloride (14 mg, 0.11 mmol). Sodium borohydride (12 mg, 0.33 mmol) was added at 0 ° C and the temperature was maintained at 0 ° C for 30 min. Then, the mixture was heated to rt and stirred overnight. The reaction was stopped by adding aqueous saturated ammonium chloride. The separated aqueous phase was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by HPLC to give the title compound (10 mg, 10%). ¾ NMR (CDC13) d: 1.1-1.2 (4H, m), 2.0 (3H, s), 2.3 (1H, m), 3.4 (2H, a), 3.8 (3H, s), 4.3 (1H, d), 4.8 (2H, d), 5.6 (1H, a), 6.4 (1H, m), 6.6 (2H, m) , 6.9 (1H, m), 7.1-7.4 (8H, m). MS m / z: 444 (M + 1) (2S, 4J¾) -IV- (4-Butyl-phenyl) -iV- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -acetamide (C-39) was prepared (2S, 4R) -N- (4-butyl-enyl) -N- [1- (4-methoxy-benzoyl) - 2-met-il-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide following the general procedure C, substituting 4-fluorobenzoyl chloride for 4-methoxybenzoyl chloride and 4-chlorophenylboronic acid for 4 butyl phenylboronic ? NMR (CDCl 3) d: 0.9 (3H, m), 1.2 (3H, d), 1.4 (3H, m), 1.6 (2H, m), 2.0 (3H, s) , 2.4 (1H, m), 2.6 (2H, m), 3.8 (3H, s), 4.8 (1H, m), 5.6 (1H, a), 6.5 ( 1H, d), 6.7 (2H, d), 7.0 (1H, m), 7.1-7.2 (7H, m), 7.4 (1H, d). MS m / z: 471 (M + 1). The C-40-C-147 compounds can be prepared by the schemes indicated in Schemes 15-16 and by the general procedures C and others described herein. Those skilled in the art will be able to recognize or ensure, using only routine experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 3: Compounds Derived from General Procedure C General procedure Scheme 15 Methyl ester of (2S, 4i¾) - ((4 - { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino.}.-phenoxy) -acetic acid (D-9). (2 S, 4R) - ((4 - { acetyl - [1- (4-methoxy-benzoyl) -2- methyl ester was prepared. methyl-1,2,3,4-ethohydro-quinolin-4-yl] -amino.} - phenoxy-acetic acid from (2S, 4R) - (2-methyl-1, 2) benzyl ester , 3,4-tetrahydro-quinolin-4-yl) -carbamic acid as shown below: (2 S, 4 R) - (2-mti 1 -?, 2, 3, 4 - tetrahydro) benzyl ester was dissolved. -quinol in 4-yl) -carbamic acid (7.6 g, 25.65 mmol) in dichloromethane (50 ml) and the remaining solution was cooled to 0 ° C. Triethylamine (14 g) was added dropwise to this solution. 3 ml) followed by freshly distilled anisoyl chloride (8.75 ml, 51.3 mmol) dissolved in dichloromethane (15 ml) The resulting reaction mixture was allowed to warm to room temperature and was stirred for 20 minutes. The mixture was partitioned between dichloromethane and sodium hydroxide 1. The extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude amide was purified by chromatography on silica gel (2: 1 hexane: ethyl acetate) yielding the pure product (10 g, 91%). The benzyl ester of (2S, 4J¾) - [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro-quinol-4-yl] -carbamic acid formed in this way ( 10 g) was dissolved in ethanol (400 ml). Palladium (10% on carbon) was added. The black suspension was stirred under a hydrogen atmosphere for 3 h. The mixture was filtered and concentrated. The crude amine was purified by filtration through a silica plug (elution with ethyl acetate gradient to 90/10 ethyl acetate / methanol) to yield the pure amine (5.17 g, 72%). (2S, 4R) - (4-amino-2-methyl-3,4-dihydro-2H-quinol ind-1-yl) - (4-methoxyphenyl) -methanone (100 mg, 0.34 ramol ), Methyl 2- (4 -bromophenoxy) -acetate (91 mg, 0.37 mmol), Pd2 (dba) 3 (17 mg, 0.02 mmol), 2-dicyclohexylphosph ino-2 '- (N, N) dimethylamino) biphenyl (8 mg, 0.00002 mol) and cesium carbonate (0.163 g, 0.0005 mol) in a round bottom flask which was then flushed with nitrogen gas through a rubber stopper. Toluene (2 ml) was injected into the flask through the rubber septum and the reaction mixture was stirred at 100 ° C for 24 h. After cooling to room temperature, the reaction mixture was filtered through Celite® and evaporated to give the crude product (0.236 g). This crude product was purified by chromatography on silica gel eluting with a gradient of 100% hexanes to 50/50 hexanes / ethyl acetate to give the title compound (37 mg, 24%). Freshly distilled acetyl chloride (0.5 ml) was added to a solution of the aniline prepared in this manner (0.037 g, 0.00008 mol) followed by diisopropylethylamine (0.0114 g, 0.015 ml, 0.088 mmol) in dichloromethane ( 0.5 ml); the mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with 1 M sodium bicarbonate. The organic phase was separated, washed three times with water and brine, dried over magnesium sulfate and evaporated. The resulting crude product was purified by chromatography on silica gel eluting with 0% to 70% ethyl acetate in hexanes, yielding the title compound (15 mg, 38%). ? NMR (CDC13) d: 1.12-1.14 (4H, m), 2.02 (3H, s), 2.18-2.43 (1H, m), 3.75 (3H, s) 3 , 82 (3H, s), 4.65 (2H, s), 4.67 -4.82 (1H, m), 5.45-5.73 (1H, broad), 6.52 (1H) , 6.68 (2H, d), 6.89-6.95 (3H, m), 7.13-7.21 (5H, m), 7.32 (1H, d). MS m / z: 504 (+ 1). Acid (2S, 42¾) - (4-. {Acetyl- [1- (4-methoxybenzoyl) -2-methyl-1, 2, 3, 4-tetrahydroquinolin-4-yl] -amino.} - phenoxy) -acetic (D-10) Acid (2S, 4i¾) - (4-. {Acetyl- [1- (4-methoxybenzoyl) -2-methyl-l was prepared, 2,3,4-tetrahydroquinolin-4-yl] -amino} -phenoxy) -acetic acid from methyl ester of acid. { 2S, 4i?) - (4 - { Acetyl- [1- (4-methoxybenzoyl) -2-methyl-l, 2,3,4-tetrahydroquinolin-4-yl] -amino) -phenoxy) -acetic acid ( 15 mg, 0.03 mmol). The methyl ester was dissolved in methanol (1 mL), sodium hydroxide (1 mL, 0.1 M in water) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was acidified with hydrochloric acid (1 M) and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed three times with water and with brine, dried over sodium sulfate, filtered and concentrated to yield the title compound (13 mg, 89%). 1 H NMR (CDCl 3) d: 1.07 (4 H, m), 1.99 (3 H, s), 2.12 -2.38 (1 H, broad), 3.7 (3 H, s), 4.61 (2H, s), 4.66 - 4.78 (1H, m), 5.47 - 5.75 (1H, broad), 6.49 (1H, d), 6.64 (2H, d), 6.86 - 6.9 (3 H, m), 7.09 - 7.16 (5H, m), 7.27 (1 H, d). MS m / z 489 (+), 490 (M + l) Acid (2S, 4i¾) -2- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl- 1,2 , 3,4-tetrahydro-quinolin-4-yl] -amino.} - phenyl) -2-methyl-propionic acid (Dl) Acid (2 S, 4R) -2 - (4 - { [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} - phenyl) -2-methyl-propionic acid by saponification of methyl ester of 2 - (4 - {- acetyl - [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} -phenyl -2-methyl-propionic acid, as written in the synthesis of (2S, 4i¾) - (4. {Acetyl - [1- (4-methoxybenzoyl) -2-methyl-1, 2, 3, 4-tetrahydroquinolin-4-yl] -amino.} - phenoxy) -acetic acid. The methyl ester was prepared following the general procedure D, substituting methyl 2- (4-bromo-phenoxy) -acetate for 2- (4-bromo-phenyl) -2-methyl-propionic acid. ? NMR (300 MHz, CD30D) d: 1.07-1.18 (m, 4H), 1.58 (s, 6H), 2.02 (s, 3H), 2.42-2.56 (m, 1H), 3.76 (s, 3H), 4.74 (ddd, 1H), 5.55 (sa, 1H) ), 6.56 (d, 1H), 6.75 (d, 2H), 6.97 (dd, 1H), 7.13-7.27 (m, 3H), 7.36 (d, 2H) 7.42-7.55 (m, 3H). Acid (2S, 4J2) -4- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino .} -2-chloro-phenyl) -4-oxo-butyric acid (D-2) (2S, 4i?) -4 - (4 - { Acetyl - [1 - (4-methoxy- benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} -2-chloro-phenyl) -4-oxo-butyric acid from the corresponding methyl ester following the procedure above for the synthesis of (2S, 4i?) - (4 - { acetyl- [1- (4-methoxybenzoyl) -2-methyl-1, 2,3,4-tetrahydroquinolin-4-yl] -amino .}. -phenoxy) -acetic. The corresponding methyl ester was prepared following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4- (4-bromo-2-chloro-phenyl) -4-oxo-butyric acid methyl ester. XH NMR (300 MHz, CD3OD) d: 1.10-1.19 (m, 4H), 2.08 (br s, 3H), 2.41-2.56 (m, 1H), 2.69-2 , 74 (m, 2H), 3.20-3.26 (m, 2H), 3.75 (s, 3H), 4.74 (ddd, 1H), 5.45-5.62 (sa, 1H) ), 6.57 (d, 1H), 6.74 (d, 2H), 6.98 (dd, 1H), 7.16 (d, 2H), 7.20-7.27 (m, 1H) , 7.42-7.49 (m, 2H), 7.60 (br s, 1), 7.73 (d, 1H). MS m / z: 549 (M + 1). (23, R) -N- (4-Dimethylsulfamoyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] - acetamide (D-3) was prepared (2S, 4J¾) -iV- (4-dimethylsulfamoyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2,3,4-tetrahydro -quinolin-4-yl] -acetamide following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4-bromo-N, JV-dimethyl-benzenesulfonamide. XH NMR (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 2.0 (3H, s), 2.3 (1H, m), 2.8 (6H, s), 3.8 (3H, s), 4.8 (1H, m), 5.6 (1H, m), 6.6 (1H , d), 6.7 (2H, d), 6.9 (1H, t), 7.2 (3H, m), 7.3 (1H, m), 7.5 (2H, d), 7 , 8 (2H, d). MS m / z: 522 (M + 1). (2S, 4J¾) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- [4- (pyrrolidine-l- sulfonyl) -phenyl] -acetamide (D-4) was prepared (2S, 4i?) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinoline- 4-yl] -N- [4 - (pyrrolidine-1-sulfonyl) -phenyl] -acetamide following the general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for l- (4-bromo-benzenesulfonyl) -pyrrolidine. XH RM (CDC13) d: 1.1 (3H, d), 1.1 (1H, m), 1.7 (4H, m), 2.0 (3H, s), 2.3 (1H, m ), 3.3 (4H, m), 3.7 (3H, s), 4.7 (1H, m), 5.6 (1H, m), 6.5 (1H, d), 6.6 (2H, d), 6.9 (1H, t), 7.3 (4H, m), 7.4 (2H, d), 7.9 (2H, d). MS m / z: 548 (M + 1). (2S, 4_¾) -N- (4-ethanesulfonyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tetrahydro-quinolin-4-yl] - Acetamide (D-5) was manufactured. { 2S, 4R) -N- (4-methanesulfonyl-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3, 4-tet ahydro-quinolin-4-yl] - acetamide following general procedure D, substituting methyl 2 - (4-bromophenoxy) -acetate for l-bromo-4-methanesul fonyl-benzene. ?? NMR (CDCl 3) 6: 1.1-1.2 (3H, m), 2.0-2.2 (4H, m), 2.3 (1H, m), 3.1 (3H, s), 3.7 (3H, s), 4.8 (1 H), 5.6-5.8 (1H, a), 6, 5 (1H, d), 6.6 (2H, d), 6.9 (1H, t), 7.1-7.3 (4H, m), 7.4 (2H, d), 8.0 (2H, d). MS m / z: 493 (M + 1). Acid (25.4K) -3- (4- { Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino .}.-phenyl) -propionic (D-6). (2S, 4R) -3 - (4 - { acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2-acid. , 3,4-tetrahydro-quinolin-4-yl] -amino.}.-Phenyl) -propionic from (2S, 4J?) - N- (4-bromo-phenyl) -N- [1- (4 -methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -acetamide. It was converted (2S, 4i?) - N- (4-bromo-phenyl) -N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4 - il] -acetamide in acrylic acid using the same procedure described in the synthesis of (±) -3 - [4 - [(4-chloro-phenyl) -propioni-1-amino] -1- (4-fluoro-benzoyl) acid ) -2-met il -1,2,3,4-tetrahydro-quinolin-6-yl] -acrylic. The reduction and saponification were carried out as in the procedure which describes the preparation of (2S, 4R) -3 - (4. {4 - [acetyl- (4-chloro-phenyl) -amino] -2-methy acid. 1 - 3, 4-dihydro-2H-quinol ina-1-carbonyl.] - phenyl) -propionic acid. ¾ NMR (CDC13 300 MHz) d 1.12 (3H, d), 1.20-1.24 (1H, m), 2.00 (3H, s), 2.22-2.38 (1H, m ), 2.52 (2H, t), 3.00 (2H, t), 3.72 (3H, s), 4.64-4.79 (1H, m), 5.44-5.70 ( 1H, m), 6.50 (1H, d), 6.65 (2H, d), 6.90 (1H, t), 7.10-7.28 (7H, m), 7.32 (1H , d). (2S, 4J¾) -3- (4-. {Acetyl- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino} - phenyl) -propionamide (D-7) was prepared (2S, 4R) -3 - (4 - { acetyl - [1- (4-methoxy-benzoyl) -2-methyl-1, 2, 3,4-tetrahydro-quinolin-4-yl] -amino.} - phenyl) -propionamide from (2S, 4J?) - 3 - (4 - { Acetyl - [1 - (4 - methoxy-benzoyl) -2-methyl-1,2,4,4-tetrahydro-quinol-4-yl] -amino.} - phenyl) -propionic acid. To a solution of 3- (4-. {Acetyl - [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -amino acid}-phenyl) -propionic (21 mg, 0.042 mmol) in dimethylformamide (200 μ?) were added HATU (24 mg, 0.063 mmol), HOBt (8.5 mg, 0.063 mmol), NH4Cl (4.5 mg , 0.084 mmol) and DI PEA (29 μ ?, 0.168 mmol). After the starting unit was consumed (2.5 hours), the mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO 3. (4 x 10 mi). The EtOAc layer was collected, dried over Na 2 SO, filtered and concentrated to yield the title compound (17.2 mg, 82%). NMR (CDCl 3 300 MHz) d 1.09 (3H, d), 1.20-1.24 (1H, m), 2.02 (3H, s), 2.22-2.38 (1H, m) ), 2.52 (2H, t), 3.00 (2H, t), 3.73 (3H, s), 4.64-4.79 (1H, m), 5.30-5.70 ( 3H, m), 6.50 (1H, d), 6.68 (2H, d), 6.91 (1H, t), 7.10-7.28 (7H, m), 7.32 (1H , d). (2S, 4R) -N- [1- (4-Methoxy-benzoyl) -2-methyl- 1, 2, 3, 4-tetrahydro-quinolin-4-yl] -N- (4-nitro-phenyl) - acetamide (D-8) (2S, 4R) -N- [1- (-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N- ( 4-nitro-phenyl) -acetamide following general procedure D, substituting methyl 2- (4-bromophenoxy) -acetate for 4-bromonitrobenzene. X H NMR (CDC13 300 MHz) d 1.12 (3 H, d), 1.20-1.24 (1 H, m), 2.07 (3H, s), 2.20-2.35 (1H, m), 3.73 (3H, s), 4.66-4.81 (1H, m), 5.50-5, 78 (1H, m), 6.55 (1H, d), 6.68 (2H, d), 6.96 (1H, t), 7.10-7.32 (4H, m), 7.46 (2H, d), 8.28 (2H, d). MS m / z: 460 (M + 1).
Table 4: Compounds Derived from General Procedure D General procedure E Scheme 16 Phenylacetamides (±) -N- (7-acetyl-6-methyl-4, 5,6,7-tetrahydrohetero [2,3-b] iridin-4-yl) -N- substituted (45) Ethyl 2-ethyl ester - (2-ethoxycarbonyl-1-methyl-ethylamino) -furan-3-carboxylic acid (38) 2-amino-furan-3-carboxylic acid ethyl ester and kut-2-enoic acid ethyl ester are dissolved in ethanol and heat to reflux in the presence of Al203, until no starting material remains, filter and concentrate. The residue is purified by flash chromatography to produce the corresponding diketone. 2- [Benzyl- (2-ethoxycarbonyl-1-methyl-ethyl) -amino] -furan-3-carboxylic acid ethyl ester (39) The synthesis is carried out using the alkylation described for the synthesis of A-164, substituting 3-methoxybenzyl bromide for benzyl bromide. 7-Benzyl-5-methyl-4-oxo-4,5,6,7-tetrahydro-furo [2,3-b] pyridine-5-carboxylic acid ethyl ester (40) To a solution of the diester in ethyl ether at room temperature, potassium tert-butoxide is added and the mixture is left stirring for 1 hour. The mixture is filtered to remove any hydrolyzed material. The solvent was removed in vacuo, yielding the potassium salt of the bicyclic ester. 7-Benzyl-6-methyl-6,7-dihydro-5H-furo [2,3-b] iridin-4 -one (41) The α-keto-ester is dissolved in 4 M HC1 in dioxane and stirred for 2 hours at room temperature. Then, 4 N HCl is added and the mixture was heated in an oil bath at 100 ° C for 12 hours. The mixture is then cooled to room temperature and neutralized with 1 N NaOH. The aqueous phase is extracted with ethyl acetate, dried over magnesium sulfate and filtered. Evaporate the solvent in vacuo and purify the residue by flash chromatography producing the corresponding ketone. Phenyl-amine (+) - (7-benzyl-6-methyl-4,5,6,7-tetrahydro-furo [2,3-b] pyridin-4-yl) -substituted (42) The synthesis of phenylamine Substituted is carried out using the procedure described for Fl, substituting the aniline for the corresponding aniline. Phenyl-substituted amide (+) - N - (7-benzyl-6-methyl-4,5,6,7-tetrahydro-furo [2,3-b] iridin-4-yl) -N- substituted (45) The synthesis of the corresponding phenylaraide is carried out using the hydrogenation and acylation processes described in general procedure B with the corresponding acid chlorides. Representative examples of compound 45 are shown in the following table. The compounds E-1-E-30 can be prepared by the schemes indicated in Schemes 18 and by the general procedures E and others described herein. Those skilled in the art will be able to recognize or ensure, using only routine experimentation, many equivalents of the specific embodiments of the invention described herein.
Table 5: Examples that use, General Procedure E Methods F N- [1- (3-Methoxy-benzoyl) -2, 2-dimethyl-1, 2, 3, 4-tetrahydroquinoline-4-yl] -N-phenyl-acetamide (Fl) N was synthesized - [1 - (3-Ethoxy-benzoyl) -2, 2 -dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide from 4 - (hydroxy-2) , 2-dimethyl-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy-phenyl) -methanone according to the reference Hamann, L. G.; Higuchi, R. I .; Zhi, L; Edwards, J. P .; ang, X; arrschke, K. B.; Kong, J. W.; Farmer, L. J.; Jones, TDJ Med. Chem 1998, 41, 623. This was worked up again to N- [1- (3-methoxy-benzoyl) -2, 2-dimethyl-1,2,3,4-tetrahydro-quinoline-4 -yl] -N-phenyl-acetamide using in situ iodide formation and displacement with the aniline according to the following procedure. To a cooled solution of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-quinolm-1-yl) - (3-methoxy-phenyl) -methanone (500 mg, 1.6 mmol) in 10 ml of dichloromethane were slowly added 0.8 ml of iodotrimethylsilane (5.6 mmol) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 6 hours. Then, the mixture was concentrated in vacuo. The residue was dissolved in 12 ml of THF. BaC03 (630 mg, 3.2 mmol) and aniline (0.17 mL, 1.92 mmol) were added. The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 4), to give (2,2 -dimethyl-4-phenylamino-3,4-dihydro-2H-quinolin- 1 - il) - (3-methoxy-phenyl) -methanone (150 mg, 24%). To a solution of (2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-quinol in-1-yl) - (3-methoxy-phenyl) -methanone in methylene chloride (5 ml) is added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M NaOH (aq.) And brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) to yield N- [1- (3-methoxy-benzoyl) -2,2-dimet il -1,2,3 , 4-tetrahydroquin-1 in-4-yl] -N-phenyl-acetamide. XH NMR (CDC13) d: 1.5 (1H, m), 1.6 (3H, s), 1.7 (3H, s), 1.9 (1H, m), 2.0 (3H, 3), 3.7 (3H, m), 5.8 (1H, m), 6.5 (1H, d), 6.6-7.1 (8H, m), 7.2 (1H, m), 7.3-7.5 (3H, d). MS m / z: 429 (M + 1). (2S, 4J?) -4-Chloro-.W-ethyl-.N- [1- (4-methoxy-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl] -benzamide (F-2) was synthesized (2S, .R) -4-chloro-N-yl-N- [1- (4-methoxy-benzoyl) -2-methyl-l, 2,3,4- tetrahydro-quinolin-4-yl] -benzamide as described in general procedure C, with the exception that after removal of the benzyl carbamate the amine was modified in the following manner. To a solution of (2S, 4J?) - (4-amino-2-methyl-3, 4-dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone (200 mg, , 68 mmol) in 20 ml of dichloromethane was added acetaldehyde (0.042 ml, 0.75 mmol). The reaction mixture was stirred for 30 min at room temperature. Then, sodium triacetoxyborohydride (0.156 g, 0.75 mmol) was added and the resulting reaction mixture was stirred at room temperature for 6 hours. N, N-diisopropylethylamine (0.3 ml, 2.3 mmol) and 4-chlorobenzoyl chloride (0.4 ml, 3.1 mmol) were added and stirred at room temperature overnight. Dichloromethane (40 ml) was added. The mixture was washed with 30 ml of sodium hydroxide (1 N). The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-dichloromethane (1: 4), giving 80 mg (24%) of the title compound. XH NMR (CDC13) d: 1.2-1.4 (7H, m), 1.7 (1H, m), 2.7 (1H, m), 3.1 (1H, m), 3.8 (3H, s), 4.2 (1H, m), 4.8 (1H, m), 6.5 (1H, d), 6.6 (2H, d), 6.8 (2H, m) , 6.9 (1H, m), 7.1-7.5 (6H, m) MS m / z: 463 (M + 1). N- [1- (3-Methoxy-benzoyl) -1,2,3,4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide (F-3) N- [1 - (3 - Me oi-benzoyl) -1,2,3,4-1-tetrahydro-quinolin-4-yl] -A- phenyl -acetamide from 1- (4-methoxy-benzoyl) -2,3-dihydro-lH-quinolin -4 -one synthesized according to the reference Bellassou-Fargeau, M. C.; Graffe, B .; Sacquet, M. C.; Maitte, P. J. de Heter. Chem. 1985, 22 (3), 713. This was worked up again at (4-hydroxy-3,4-dihydro-2H-quinol in- 1-yl) - (3-methoxy-phenyl) -methanone by reduction of the ketone in the alcohol and in situ formation of the iodide and displacement with the aniline according to the following procedure. To a solution of 1- (3-methoxy-benzoyl) -2,3-dihydro-lH-quinolin-4 -one (310 mg, 1.1 mmol) in 5 ml of methanol was added 410 mg of sodium borohydride ( 4.4 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 2) to give (4-hydroxy-3,4-dihydro-2H-quinolin-1-yl). ) - (3-methoxy-phenyl) -raetanone (215 mg, 69%). This was worked up again to (3-methoxy-phenyl) - (4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) -raetanone using the following procedure. To a cooled solution of (4-hydroxy-3,4-dihydro-2-yl-quinolin-1-yl) - (4-methoxy-phenyl) -methanone in dichloromethane was slowly added iodotrimethylsilane at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 6 hours. Then, the mixture was concentrated in vacuo. The residue was dissolved in THF. BaC03 and aniline were added. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (1: 4), to give (4-phenylamino-3,4-dihydro-2H-quinolin-1-yl) - (3-methoxy) phenyl) -methanone To a solution of (4-phenylamino-3, -dihydro-2H-quinolin-1-yl) - (4-methoxy-phenyl) -methanone in methylene chloride was added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with NaOH 1 (aq) and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by chromatography on silica gel (50% hexanes / 50% ethyl acetate) yielding (+) - N - [1- (3-methoxy-benzoi 1) -1,2,3,4 - tetrahydro-quinolin-4 -yl] -N-pheny1 -acetamide. XH NMR (CDC13) d: 1.2 (1H, m), 1.9 (3H, s), 2.1 (1H, m), 2.3 (1H, m), 3.5 (1H, m ), 3.7 (3H, m), 4.1 (1H, m), 6.4 (2H, m), 6.6 (1H, m), 6.8-7.3 (6H, m) , 7.4 (3H, m), 7.5 (1H, d). MS m / z: 401 M + 1). Table 6: Structurally Diverse Series The Described Compounds Inhibit the Binding of PGD2 to CRTH2 This membrane radioligand binding assay assesses the ability of the compounds to inhibit the binding of [3H] Prostaglandin D2 (PGD2) to the cloned human CRTH2 receptor stably expressed in HEK- c. 293 (expressing the human CRTh2 receptor and the subunit? Or the heterotrimeric G protein 16, prepared in Biosignal Corrtpany) using the Scintillation Proximity Assay. A binding buffer containing 50 mM Tris-HCl (pH 7.5), 5 mM MgCl2 and 1 mM EDTA was prepared immediately before the assay was performed. A bead / membrane solution was prepared at two times the final assay concentration comprising membranes (membranes acquired in Biosignal) of cloned HEK-293 c to express the CRTH2 receptor bound to [3 H] PGD2 at two times the final assay concentration and stored on ice before addition to the w. Cold PGD2 was prepared at twenty times the final assay concentration and stored on ice before addition to the w to define non-specific binding (NSB). For this test, Corning No. 3653 plates were used. Concentrations of stock solution of 10 mM of the compounds in 100% DMSO were prepared and stored at room temperature. A 10-point concentration-response curve was then constructed for each compound, starting at 10 μ? (final test concentration). The compounds were prepared at a concentration 40 times that of the final test with nine consecutive 3-fold dilutions. 0.1 μ? from each concentration of the compound to the appropriate wof plate 384 and 2 μ? PGD2 cold to the w that defined the NSB. Then 20 μ? Were added to each w of [3H] PGD2 and subsequently 20 μ? of 2x the bead / membrane solution. The plates were allowed to incubate at room temperature for about 2 hours and then counted in a Packard Topcount using the SPA tritium protocol for 1 minute / w The percentage inhibition of PGD2 binding (PGD2 was used at the KD value or rr.enor) to the membranes of HEK-293 c was determined, the assay was always carried out in duplicate for n = l for a total of n = 2 Figure 1: ¾ of the binding of PGD2 to CRTH2 (μ?) Compounds A-3, A-11, A-16, A-17, A-20, A-24, A-35, A-49, A-51, A-54, A-55, A-67, A-70, A-72, A-73, A-81, A-82, A-120, A-130, A-131, A-132, A-143, A-144, A-147, A- 153, A-156, A-157, A-159, B-7, B-9, B-ll, B-13, B-18, B-20, B-26, B-28, B-34, B-39, B-40, B-47, B-51, B-58, B-59, B-63 to B-66, B-68, B-70, B-73, B-74, B- 84, B-86, B-97, B-101 to B-112, C-33, C-37, C-38, Dl, D-2, D-6, D-10, F-3 have a KL < 10 μ? Compounds A-B, A-53, A-58, A-124, A-126, A-154, B-53, B-100, F-1 have one? < 60 μ? The remaining compounds have a K << 1 μ? While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes may be made in the form and in the details thereof without departing from the scope of the invention encompassed by the claims. Attached

Claims (1)

  1. CLAIMS 1. A method for inhibiting CRTH2 in a subject that needs to inhibit CRTH2, which comprises administering to the subject an effective amount of a compound represented by the following structural formula: a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted monocyclic aromatic ring; R is -Xi-R1; R x is -X 2 -R 4 and R 3 is an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; or -NRXR3, tornados with a, is a heterocyclic group that: contains non-aromatic and optionally substituted nitrogen; X is -C (0) - or -C (R2) 2-; each of Xx and X2 are independently a bond, S (O), S (0) 2, C (0) or C (0) NH; R1 is H or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; with the proviso that when Xx is a bond, SO or S02, then R1 is not H; each R2 is independently -H, -X -R8 or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R4 is -H, -X6-R ~ ° or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; with the proviso that when X2 is a bond, SO or S02, then R4 is not H; each of X4 and X6 are independently a linear or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, -OH, = 0, C1-C3 alkoxy, nitro and cyano; each of R 5 and R 6 is independently H or C 1 -C 3 alkyl; each of R8 and R10 are independently H, -C (0) 0R 'or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; wherein, the optional substituents in the aliphatic group, the cycloaliphatic group or the non-aromatic heterocyclic group are from one to three groups each independently selected from the group consisting of halo, R11, = 0, = S, = NNHR *, = NN (R *) 2, = NNHC (0) R *, = NNHC02 (alkyl), = NNHS02 (alkyl) y = NR *; the optional substituents on the unsaturated carbon atoms of the aromatic group is R11; optional substituents on a nitrogen atom of the aromatic group or the nitrogen atom of the nitrogen-containing non-aromatic heterocyclic group are from one to three groups each independently selected from the group consisting of R +, -N (R +) 2, -C (0) R +, -C02 R +, -C (0) C (0) R +, -C (0) CH2C (0) R \ -S02 R +, -S02 N (R +) 2, -C (= S) N (R +) 2, -C (= NH) -N (R +) 2 and -NR + S02R +; R11 is one to four substituents each independently selected from the group consisting of halo, R ° (-OH, -0R °, -SH, -SR °, 1,2-methylenedioxy, 1,2-ethylenedioxy, -OH protected, phenyl, [R12] -phenyl, -O (phenyl), -0 ([R12] -phenyl), -CH2 (phenyl), -CH2 ([R12] -phenyl), -CH2CH2 (phenyl), CH2CH2 ([R12] -phenyl), -N02, -CN, -N (R ') 2, -NR'C02R °, -NR'C (0) R °, -NR' NR 'C (O) R ° , -N (R ') C (0) N (R') 2, -NR 'NR' C (O) N (R ') 2, NR'NR'C02R °, -C (0) C (0) R °, -C (O) CH2C (0) R ', -C02R', -C (0) R °, -C (0) N (R ') 2, -0C (O) N (R') 2 , -S (0) 2R °, -S02N (R ') 2, -S (0) R', NR'S02N (R ') 2, -NR'S02R °, -C (= S) N (R' ) 2, - (CH2) and N (R ') 2, -C (= NH) -N (R') 2, - (CH2) and C (0) N (R ') 2, - (CH2) and NHC (0 ) R 'or - (CH2) and NHC (0) CH (VR') (R '); R 'is H, R °, -C02R °, -S02R ° or -C (0) R °; and is 0-6; V is Ci-C6 alkylene; each R * is independently H, an aliphatic group or an aliphatic group substituted with R12; R + is H, phenyl, [R12] -phenyl, -O (phenyl), -0 ([R12] -phenyl), -CH2 (phenyl), -CH2 ([R12] -phenyl), a heteroaryl group, a group non-aromatic heterocyclic, an aliphatic group or an aliphatic group substituted with R12; R ° is an aliphatic group, a cycloaliphatic group, an aromatic group, an aralkyl group or a non-aromatic heterocyclic group, each group being optionally substituted with R12; R is from one to four substituents each independently selected from the group consisting of halo, Ci-C6 alkyl, (halo) rC1-Ce alkyl, C3-C8 cycloalkyl, (halo) C3-C8 cycloalkyl, -CN , -CF3, -CHF2, -CH2F, -OCF3 (-OCHF2, -OCH2F, -0R ', -OR13C (0) R', -C (0) OR ', - C (O) N (Rls) 2, N (R16) 2, -N02, -NR16C (0) R ', -NR16C (O) OR', -NR16C (O) N (R16) 2, NR1SS02R17, -S (0) qR17, -R13NR16C (0) R ', -R13C (0) R', -R13NR1SC (O) OR ', tetrazolyl, imidazolyl or oxadiazolyl; R 13 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; each R16 is independently R 'or benzyl; R17 is R13 or -CF3; q is 0-2; and r is 1 -3, 2. The method of claim 1 wherein: Ring A is phenyl or [R 11] -phenyl; X is -CHR2 -; each of R1 and R3 is independently an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R2 is H or an optionally substituted Ci-C4 alkyl group, a C'i-C4 alkyl group, alkoxymethylene or a C3-C3 cycloalkyl group; R 4 is an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; and each of R5 and Rs is H. The method of claim 2 wherein R3 is an optionally substituted aromatic group. The method of claim 3 wherein the compound is represented by the following structural formula: wherein each of Ring A, R1, R2 and R4 are independently defined in claim 2, 5. The method of claim 4 wherein: R1 is H or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R3 is phenyl or [R11] -phenyl; R4 is H, -CH2C (0) R14, -CH2R15, -CH2OR14 or an optionally substituted Cx-C3 alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 14 is H or an optionally substituted alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; and R15 is an optionally substituted aromatic group, cycloalkyl group or non-aromatic heterocyclic group; where R11 and each of the optional substituents are independently defined in claim 1, 6. The method of claim 1 wherein Ring A is thiophene, furan, pyridine, pyrazole, pyrrole, [2, 3] pyrimidine, [3, 4] pyrimidine, [4, 5] irimidine, [5,6] pyrimidine, oxazole, isoxazole or 1,2,3-triazole, each group being optionally substituted with R 11, 7L0 The method of claim 6 wherein: X is -CHR2-Rx is -X2-R4; each of R1 and R3 is independently an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R2 is H or an optionally substituted Ci-C4 alkyl group, Ci-C4 alkyl group, alkoxymethylene or C3-C6 cycloalkyl group; R 4 is an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; and each of R5 and R6 is H. 8. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic ring; R is -Xi-R1; Rx is -X2-R4 and R3 is an optionally substituted aromatic group; or - RXR3, taken together, is a heterocyclic group containing non-aromatic and optionally substituted nitrogen; X is -C (O) - or -C (R2) 2 -; each of Xi and X2 is independently a bond, S (0), S (0) 2, C (O) O C (0) NH; R1 is H or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group; with the proviso that when Xx is a bond, SO or S02, then R1 is not H; each R2 is independently H, -X4-R8 or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; R4 is H, -X6-R10 or an optionally substituted aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; with the proviso that when X2 is a bond, SO or S02, then R4 is not H; each of X4 and X6 is independently a linear or branched hydrocarbyl group optionally substituted with one or more groups selected from the group consisting of halo, -OH, = 0, Ci-C3 alkoxy, nitro and cyano; each of R 5 and R 6 is independently H or C 1 -C 3 alkyl; and each of R8 and R10 is independently H, -C (0) 0R 'or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; wherein, the optional substituents in the aliphatic group, the cycloaliphatic group or the non-aromatic heterocyclic group are from one to three groups each independently selected from the group consisting of halo, R11, = 0, = S, = NNHR *, = NN (R *) 2, = NNHC (0) R *, = NNHC02 (alkyl), = NNHS02 (alkyl) y = NR *; the optional substituents on the unsaturated carbon atoms of the aromatic group is R11; optional substituents on a nitrogen atom of the aromatic group or the nitrogen atom of the nitrogen-containing non-aromatic heterocyclic group are from one to three groups each independently selected from the group consisting of R +, -N (R +) 2, -C (0) R +, -C02 R +, -C (0) C (0) R +, -C (O) CH2C (O) R +, -S02 R +, -S02 N (R +) 2, -C (= S) N (R +; 2, -C (= NH) -N (R +) 2 and -NR + S02R +; R11 is one to four substituents each independently selected from the group consisting of halo, R °, -OH, -0R °, -SH, -SR °, 1,2-methylenedioxy, 1,2-ethylenedioxy, -OH protected, phenyl, [R] -phenyl, -O (phenyl), -0 ([R 12] -phenyl), -CH 2 ( phenyl), -CH2 ([R12] -phenyl), CH2CH2 (phenyl), -CH2CH2 ([R12] -phenyl), -N02, -CN, -N (R ') 2, NR'C02R °, -NR'C (0) R °, -NR' NR 'C (0) R °, -N (R ') C (0) N (R') 2, NR'NR 'C (0) N (R') 2, -NR 'NR' C02R °, -C (0 ) C (0) R °, -C (O) CH2C (0) R ', -C02R', -C (0) R °, -C (0) N (R ') 2, -0C (0) N (R ') 2, -S (0) 2R °, -S02N (R') 2, -S (0) R ', -NR'S02N (R') 2, -NR'S02R °, -C (= S) N (R ') 2, - (CH 2) and N (R') 2, - C (= NH) - N (R ') 2, - (CH 2) and C (O) N (R') 2, - (CH2) and NHC (O) R 'or (CH2) and NHC (0) CH (VR') (R '); R 'is H, R °, -C02R °, -S02R ° or -C (0) R °; and is 0-6; V is Ci-C6 alkylene; each R * is independently H, an aliphatic group or an aliphatic group substituted with R12; R + is H, phenyl, [R12] -phenyl, -O (phenyl), -0 ([R12] -phenyl), -CH2 (phenyl), -CH2 ([R12] -phenyl), a heteroaryl group, a group non-aromatic ico heterocycle, an aliphatic group or an aliphatic group substituted with R12; R ° is an aliphatic group, a cycloaliphatic group, an aromatic group, an aralkyl group or a non-aromatic heterocyclic group, each group being optionally substituted with R12; R12 is one to four substituents each independently selected from the group consisting of halo, Ci-C6 alkyl, (halo) rCi-C6 alkyl, C3-C8 cycloalkyl, (halo) C3-C8 cycloalkyl, -CN, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -0CH2F, -0R ', -0R13C (0) R', -C (0) 0R ', -C (O) N (R16) 2, N (R16) 2, -NO2, -NR16C (0) R ', -NR16C (O) 0R', -NR16C (0) N (R16) 2, NR16S02R17, -S (0) qR17, -R13NR16C (O) R ', - RI3C (0) R ', -R13NR16C (O) OR', tetrazolyl, imidazolyl or oxadiazolyl; R 13 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; each R1S is independently R 'or benzyl; R17 is R13 or -CF3; q is 0-2; and r is 1-3; with the proviso that the compound is not 2-methyl-N-phenyl- [1, 2,3,4-tetrahydro-2-methyl-1- (2-methyl-1-oxobutyl) -4-quinolinyl] -but measure; N- (1-Acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-heptamide; W-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (1-oxo-3-phenylpropyl) -4-quinolinyl] -benzenepropanamide; N-phenyl- [1,2,3,4-tetrahydro-2-methyl-1- (3-nitrobenzoyl) -4-quinolinyl] -hexanamide; N- [1,1'-biphenyl] 3-yl-N- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -iV- (4-nitrophenyl) -heptanamide; N- (1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl) -N- (4-methoxyphenyl) -2-methyl-propanamide; N- [1- (4-fluorobenzoyl) 1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-butanamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -pentanamide; 2-ethyl-N- [1- (2-ethyl-1-oxobutyl) 1,2,3,4-tetrahydro-2, 8-dimethyl-4-quinolinyl] -W- (2-methylphenyl) -butanamide; N- [1- [(4-fluorophenyl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N- phenyl-propanamide; N-phenyl- [1, 2, 3, 4-tetrahydro-2-methyl-1 - (4-nitrobenzoyl) -4-quinolinyl] -octanamide; W-cyclohexyl -4 [(Hexylamino) carbonyl] phenylamino] -3,4-dihydro-2-methyl-1 (2H) -quinolinecarboxamide; N- [1- (4-ethylbenzoyl) -1,2,3,4-tetrahydro-2,8-dimethyl-4-quinolinyl] -N- (2-methylphenyl) -3- (4-nitrophenyl) -2- propenamide; 3- (4-methoxyphenyl) -N- phenyl-N- [1,2,3,4-tetrahydro-l- [3- (4-methoxyphenyl) -l-oxo-2-propenyl] -2-ethyl--4 -quinolinyl] -2 -propenamide; acid 4 [(etoxyoxoacet il) phenylamino] -3,4-dihydro-2-met-il-V-oxo-ethyl ester-1 (2H) -quinol inaacetic; N- [1- (3-cyclohexyl-1-oxopropyl) -1,2,3,4-tetrahydro-2-methyl-4-quinol-inyl] -N-phenyl-cyclohexanopropanamide 4- (acetylphenylamino) -3,4-dihydro - 2-met il -gamm -oxo- 1 (2H) -quinoline-pentanoic acid; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -2,2-dimethyl-N-phenyl-propanamide; IV- (1-benzoyl-6-bromo-1,2,3,4-etrahydro-2-methyl-4-quinolinyl) -JV-phenyl-pentanamide; N- [1- (2-furanylcarbonyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -JV-phenyl-acetamide; 2-methyl-IV-phenyl-IV- [1,2,3,4-tetrahydro-1 - (3-methoxybenzoyl) -2-methyl-4-quinolinyl] -propanamide; N- [1- [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) acetyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N- feni 1 -aceamide; 2,2,2-trifluoro-W-phenyl-IV- [1,2,3,4-tetrahydro-1- (3-methoxybenzoi-1) -2-methyl--quinolinyl] -acetamide; 2-ethyl-JV- [1- (2-ethyl-l-oxobutyl) -1,2,3,4-tetrahydro-2-methyl-4-quinol-inyl] -N-phenyl-butanamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N- (3-methoxyphenyl) -acetamide; N-phenyl-N- [1, 2, 3, 4-tetrahydro-2-methyl-l- (1-oxohexyl) -4-quinol inyl] -acetamide; N- (1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -W-phenyl-2-thiophenecarboxamide; N- [1- (2-fluoro-benzoyl-1) -1,2,4,4-tetrahydro-2-methyl-4-quinolinyl] -iV-phenyl-hexanamide; phenyl-N- [1,2,3,4-te-ahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamide; N-phenyl-JV- [1, 2, 3, 4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -hexanamide; N- [1- (cyclopropylcarbonyl) -1,2,3,4-ethohydro-2-methyl-4-quinolinyl] -N-phenyl-cyclopropanecarboxaride; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinol inyl) -N- (4-methyl-phenyl) -acetamide; 2-methyl-N-phenyl-JV- [1, 2, 3, 4-tetrahydro-2-methyl-1 - (2-methyl-l-oxopropyl) -4-quinolinyl] -propanamide, - JV-phenyl- IV [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -2- 1 iofenocarboxamide; 1- (3,5-dinitrobenzoyl) -JV formyl-1, 2,3,4-tetrahydro-2-methyl-JV-phenyl-4-quinol inamine; JV [1- (4-chloro-3-n-robenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; JV-phenyl-JV- [1,2,3,4-tetrahydro-2-methyl-l- (3-nitrobenzoyl) -4-quinolinyl] -acetamide; IV-phenyl JV- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-met il-4 -quinol inyl] -hexanamide; JV- [1- (2-furanylcarbonyl) -1,2,3,4-tetrahydro-2-met i 1 -4 -quinol inyl] -JV-phenyl-2-furancarboxamide; JV-phenyl-JV- [1,2,3,4-tetrahydro-2-methyl-1 - (1-oxopropyl) -4 -quinol inyl] -acetamide; iV-phenyl-iV- [1,2,3,4-te rahydro-1 - [3- (4-methoxyphenyl) -l-oxo-2-propenyl] -2-methyl-4-quinolinyl] -acetamide; 3- (2-furanyl) -IV- [1- [3- (2-furanyl) -l-oxo-2-propeni 1] -1,2,3,4-tetrahydro-2-met-il-4-quinol inyl] -JV-phenyl-2-propenamide; N- [1 - [2 - (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] -1,2,3,4-tetrahydro-2 -methyl-4-quinolinyl] -JV-phenyl-octanamide; JV- [1- (-chlorobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinol ini 1] -JV-phenyl-1-acetamide; Relative stereochemistry of JV-pheni 1 -JV- [(2J ?, 4S) -1,2,4,4-tetrahydro-2-methyl-1- (1-oxopropyl) -4-quinolinyl] -acetamide; Relative stereochemistry of JV- [(2J ?, 4S) -1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -2-methyl-JV-phenyl-propanamide; Relative stereochemistry of N- [(2R, 4 S) -1-acet-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-hexanamide; Relative stereochemistry of N- [(2í? 4 S) -1-acet-1-l, 2,3, 4-tetrahydro-2-methyl-4-quinol inyl] -JV-phenyl-propanamide; Relative stereochemistry of N- [(2R, 4 S) -1-ace il-1, 2, 3, 4-tetrahydro-2-methyl-4-quinol inyl] -JV-phenyl-1-heptanamide; Relative stereochemistry of N- [(2R, 4S) -1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -2, 2-dinethyl-N-phenyl-propanamide; N- [1- (3-fluorobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N- [1- [4- (1,1-dimethylethyl) benzoyl] -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; - (1-acetyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinol inyl) -2-met i 1 -N-phenyl-propanamide; 2,2, 2-trifluoro-N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1- (trifluoroacetyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N- [(2R, iS) -1-acetyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -2, 2-dimethyl-N-phenyl-propanamide; Relative stereochemistry of N- [(2R, 4S) -1-acetyl -1, 2, 3, 4-tetrahydro-2-methyl-4-quinol inyl] -N-phenyl-butanamid; Relative stereochemistry of N- [(2R, 4S) -1-benzoyl -1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; Relative stereochemistry of N-phenyl-N- [(2R, 4S) -1, 2, 3, 4-tetrahydro-2-methyl-1- (1-oxo-heptyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N-phenyl-N- [(2R, 4S) -1, 2, 3, 4-tetrahydro-2-methyl-1- (1-oxohexyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N- [(2R, 4S) -l-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-pentanamide; iV- phenyl-N- [1,2,3, 4-tetrahydro-2-methyl-1 - (1-oxo-3-phenyl-2-propenyl) -4-quinolinyl] -acetamide; Relative stereochemistry of N- [(2R, 4 S) -1-benzoyl-1, 2, 3, 4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-heptanamide; Relative stereochemistry of N- [(2R, S) -1-acetyl -1, 2,3,4-tetrahydro-2-methyl-4-quinol-inyl] -phenyl-acetamide; Relative stereochemistry of N- [[2R, 4S) -1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-pentanamide; iV-phenyl-iV- [1,2,3,4-tetrahydro-2-methyl-1 - (tricyclo [3, 3, 1, 13, 7] dec-1-ylcarbonyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-met il-1 - (1-oxopropyl) -4 -quinolinyl] -propanamide; N-phenyl-N- [1, 2, 3, 4-tetrahydro-2-methyl-1 - (2-thienylcarbonyl) -4 -quinolinyl] -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -2-furancarboxamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (4-methoxybenzoyl) -2-methyl-4-quinolinyl] -acetamide; N- [1 - (3,5-dinitrobenzoyl) -1,2,3,4-tetrahydro-2-methyl-4-quinolinyl] -N-phenyl-acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1 - (4-nitrobenzoyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (2-iodobenzoyl-1) -2-methyl-4-quinolinyl] -acetamide; N-phenyl-N- [1, 2, 3, 4-tetrahydro-2-methyl-1 - (2-methyl-1-oxopropyl) -4-quinolinyl] -acetamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1 - [(4-methylphenyl) sulfonyl] -4 -quinolinyl] -acetamide; N-phenyl-N [1,2,3, -tetrahydro-2-methyl-1- [(4-nitrophenyl) methyl] -4-quinolinyl] -acetamide; N-phenyl- [1,2,3,4-tetrahydro-1- (3-methoxybenzoyl) -2-met-l-4-quinol inyl] -acetamide; N- (1-acetyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-butanamide; N-phenyl-N- [1,2,3,4-tetrahydro-2-methyl-1 - (1-oxobutyl) -4-quinolinyl] -acetamide; N- (1-benzoyl-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-hexanamide; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-pentanamide; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-propanamide; 1-benzoyl-l, 2,3,4-tetrahydro-4- (N-phenylacetamido) quinal idine; N- (1-acetyl-6-bromo-1, 2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-acetyl-1,2,3,4-tetrahydro-2-methyl-6-nitro-4-quinolyl) -acetanyl ida; N- (1 -acet i 1 -6-chloro-1, 2,3,4-tetrahydro-2-methyl-4-quinolyl) -acetani 1-ida; N- (1 -acetyl 1 - 1, 2, 3, -tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-6-bromo-1,2,3,4-tetrahydro-2-methyl-4-quinol inyl) -N-phenyl-acetamide; N- (1-benzoyl-6-chloro-1,2,3,4-tetrahydro-2-methyl-4-quinolinyl) -N-phenyl-acetamide; N- (1-benzoyl-1,2,3,4-tetrahydro-2-methyl-4-quinolyl) -iV-phenylbutanamide; N-phenyl-N- [1,2,3,4-tetrahydro-1- (3-fluorobenzoyl-1) -2-methyl-4-quinolinyl] -hexanamide; N- [1- (3-chloro-benzoyl) -2-methyl-5-l, 2, 3, 4-tetrahydro-quinolin-4-yl] -N-phenyl-acetamide; N- [1- (4-fluoro-benzoyl) -2-methyl-6-nitro-l, 2,3,4-tetrahydro-quinolin-4-yl] -iV-phenyl-acetamidopentanoic acid; (l-benzoyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-quinol-4-yl) -phenyl-amide; N- (1-benzoyl-6-chloro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide; N- [6-chloro-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-tetrahydro-quinol-4-yl] -N-phenyl-acetamide; N- [6-bromo-1- (4-fluoro-benzoyl) -2-methyl-1,2,3,4-ehydro-quinolin-4-yl] -N-phenyl-acetamide; N- (1-benzoyl-6-nitro-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -N-phenyl-acetamide; N-15 (1-benzoyl-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl) -IV-phenyl-butyramide; N- [1 - (3-methoxy-benzoyl) -2-methyl-1, 2,3, 4-tetrahydro-quinol-4-yl] -2,2-dimethyl-N-phenyl-propionamide. 9. The compound of claim 8 wherein: X is -CHR2-; R2 is H, methyl or ethyl; R3 is an optionally substituted aromatic group; and each of R5 and R6 is H. 12) 5. The compound of claim 9 wherein the compound is represented by the following structural formula: wherein each of Ring A, R1 and R4 is independently defined in claim 8. 11. The compound of claim 10 wherein: R1 is H or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R3 is phenyl or [R11] -phenyl; R4 is H, -CH2C (0) R14, -CH2R15, -CH20R14 or an optionally substituted Ci-C3 alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; R 14 is H or an optionally substituted alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group; and R5 is an optionally substituted aromatic group, cycloalkyl group or non-aromatic heterocyclic group; where R11 and each of the optional substituents are independently defined in claim 8. 12. The compound of claim 10 wherein ring A is phenyl or [R] -phenyl, wherein R is in the five, six, seven and / or eight position; R1 is R18; and R 4 is R 18, C 1 -C 4 alkyl, -CH 2 OH, -CH 2 OCH 3, -CH 2 OCH 2 CH 3, -CH 2 CH 2 OCH 3 or -CH 2 CH 2 OCH 2 CH 3; and R18 is phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, thiazolyl, benzyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, 10 benzomorpholinyl, benzopyrazolyl, indolyl, -CH2- (N-pyridyl), -CH2-furanyl, -CH2-thiophenyl, -CH2-isoxazolyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-pyrrolyl, -CH2- benzofuranyl, -CH2-tetrazolyl, -CH2-thiazolyl, -CH2- tetrazolyl, -CH2-benzothiazolyl, -CH2-benzimidazolyl, -CH2-O-phenyl 15, -CH2C (O) - phenyl, naphthalimidyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or cyclopropyl optionally substituted; where R11 and each of the optional substituents are independently defined in claim 8. The compound of claim 12 wherein: Ring A is phenyl or [R11] -phenyl, where R11 is in the six position and / or seven; R1 is phenyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, benzotriazolyl or benzomorpholinyl, each group optionally substituted by R11; R3 is [R11] -phenyl; and R 4 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tere-butyl, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3; where R is defined in claim 8, The compound of claim 12 wherein R1 is thiophenyl, [R11] -thiophenyl, isoxazolyl, [R11] -isoxazolilo, pyridinyl, [R11] pyridinyl, benzotriazolyl, [R11] -benzotriazolilo, benzomorpholinyl or [R11] -benzomorfolinilo, wherein R11 is defined in claim 8; or R1 is phenyl or [R11] -phenyl, wherein R11 is halo, -OR °, N (R ') 2 / oxazolyl or R3 is [R11] -phenyl, where R11 is Br, Cl, -CH3, -N (R ') 2, -NHC (0) OR', -S (0) 2CH3, -S (0) 2N (R ' ) 2 or - (CH2) and C (O) N (R ') 2; and R 4 is methyl, ethyl or -CH 2 OCH 3; where each of R ° and R 'are independently defined in claim 8. 15. The compound of claim 14 wherein R3 is [R11] -phenyl, wherein R11 is a para-position substituent. 16. The compound of claim 8 wherein: X is -CHR2; and R2 and NRXR3 are in a cis configuration with each other; wherein each of R2, Rx and R3 is independently defined in claim 8. 17. The compound of claim 16 wherein the cis configuration is 2S, 4R or 2i¾, 4S: 18. The compound of claim 8 which is represented by a structural formula selected from the group consisting of: a pharmaceutically acceptable salt thereof 19. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable diluent, excipient or vehicle. 20. A method for inhibiting CRTH2 in a subject that needs to inhibit C TH2, which comprises administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8. 21. A method for inhibiting DP in a subject in need of DP inhibition, comprising administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8. 22. A method for treating an inflammatory disease, disorder or symptom in a subject in need of treatment, comprising administering to the subject an effective amount of the compound or pharmaceutical salt of claim 8. 23. The method of claim 22, wherein the inflammatory disease, disorder or symptom is allergic rhinitis, allergic asthma, atopic dermatitis, chronic obstructive pulmonary disorder, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease or a skin disorder. 24. The method of claim 23, wherein the inflammatory disease, disorder or symptom is allergic rhinitis or allergic asthma.
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